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Filters applied: from 2022/12/26 - 2023/1/31.

1. CA Cancer J Clin. 2023 Jan;73(1):17-48. doi: 10.3322/caac.21763.

Cancer statistics, 2023.

Siegel RL(1), Miller KD(1), Wagle NS(1), Jemal A(1).

Author information:

(1)Surveillance and Health Equity Science, American Cancer Society, Atlanta,

Georgia, USA.

Each year, the American Cancer Society estimates the numbers of new cancer cases

and deaths in the United States and compiles the most recent data on

population-based cancer occurrence and outcomes using incidence data collected

by central cancer registries and mortality data collected by the National Center

for Health Statistics. In 2023, 1,958,310 new cancer cases and 609,820 cancer

deaths are projected to occur in the United States. Cancer incidence increased

for prostate cancer by 3% annually from 2014 through 2019 after two decades of

decline, translating to an additional 99,000 new cases; otherwise, however,

incidence trends were more favorable in men compared to women. For example, lung

cancer in women decreased at one half the pace of men (1.1% vs. 2.6% annually)

from 2015 through 2019, and breast and uterine corpus cancers continued to

increase, as did liver cancer and melanoma, both of which stabilized in men aged

50 years and older and declined in younger men. However, a 65% drop in cervical

cancer incidence during 2012 through 2019 among women in their early 20s, the

first cohort to receive the human papillomavirus vaccine, foreshadows steep

reductions in the burden of human papillomavirus-associated cancers, the

majority of which occur in women. Despite the pandemic, and in contrast with

other leading causes of death, the cancer death rate continued to decline from

2019 to 2020 (by 1.5%), contributing to a 33% overall reduction since 1991 and

an estimated 3.8 million deaths averted. This progress increasingly reflects

advances in treatment, which are particularly evident in the rapid declines in

mortality (approximately 2% annually during 2016 through 2020) for leukemia,

melanoma, and kidney cancer, despite stable/increasing incidence, and

accelerated declines for lung cancer. In summary, although cancer mortality

rates continue to decline, future progress may be attenuated by rising incidence

for breast, prostate, and uterine corpus cancers, which also happen to have the

largest racial disparities in mortality.

© 2023 The Authors. CA: A Cancer Journal for Clinicians published by Wiley

Periodicals LLC on behalf of American Cancer Society.

DOI: 10.3322/caac.21763

PMID: 36633525 [Indexed for MEDLINE]

2. Nat Cell Biol. 2023 Jan;25(1):159-169. doi: 10.1038/s41556-022-01049-w. Epub

2023 Jan 12.

Multiplexed screens identify RAS paralogues HRAS and NRAS as suppressors of

KRAS-driven lung cancer growth.

Tang R(#)(1), Shuldiner EG(#)(2), Kelly M(3)(4), Murray CW(3), Hebert JD(1),

Andrejka L(1), Tsai MK(1)(3), Hughes NW(1), Parker MI(5)(6), Cai H(1), Li YC(7),

Wahl GM(7), Dunbrack RL(5), Jackson PK(3)(4), Petrov DA(2)(3)(8), Winslow

MM(9)(10)(11).

Author information:

(1)Department of Genetics, Stanford University School of Medicine, Stanford, CA,

USA.

(2)Department of Biology, Stanford University, Stanford, CA, USA.

(3)Cancer Biology Program, Stanford University School of Medicine, Stanford, CA,

USA.

…

Oncogenic KRAS mutations occur in approximately 30% of lung adenocarcinoma.

Despite several decades of effort, oncogenic KRAS-driven lung cancer remains

difficult to treat, and our understanding of the regulators of RAS signalling is

incomplete. Here to uncover the impact of diverse KRAS-interacting proteins on

lung cancer growth, we combined multiplexed somatic CRISPR/Cas9-based genome

editing in genetically engineered mouse models with tumour barcoding and

high-throughput barcode sequencing. Through a series of CRISPR/Cas9 screens in

autochthonous lung cancer models, we show that HRAS and NRAS are suppressors of

KRASG12D-driven tumour growth in vivo and confirm these effects in oncogenic

KRAS-driven human lung cancer cell lines. Mechanistically, RAS paralogues

interact with oncogenic KRAS, suppress KRAS-KRAS interactions, and reduce

downstream ERK signalling. Furthermore, HRAS and NRAS mutations identified in

oncogenic KRAS-driven human tumours partially abolished this effect. By

comparing the tumour-suppressive effects of HRAS and NRAS in oncogenic KRAS- and

oncogenic BRAF-driven lung cancer models, we confirm that RAS paralogues are

specific suppressors of KRAS-driven lung cancer in vivo. Our study outlines a

technological avenue to uncover positive and negative regulators of oncogenic

KRAS-driven cancer in a multiplexed manner in vivo and highlights the role RAS

paralogue imbalance in oncogenic KRAS-driven lung cancer.

© 2023. The Author(s), under exclusive licence to Springer Nature Limited.

DOI: 10.1038/s41556-022-01049-w

PMID: 36635501 [Indexed for MEDLINE]

3. Nat Med. 2023 Jan;29(1):258-269. doi: 10.1038/s41591-022-02110-9. Epub 2023 Jan 5.

T cell receptor repertoires associated with control and disease progression

following Mycobacterium tuberculosis infection.

Musvosvi M(#)(1), Huang H(#)(2), Wang C(2), Xia Q(2), Rozot V(1), Krishnan A(3),

Acs P(3), Cheruku A(3), Obermoser G(3), Leslie A(4)(5)(6), Behar SM(7), Hanekom

WA(1)(4)(5), Bilek N(1), Fisher M(1), Kaufmann SHE(8)(9)(10), Walzl G(11),

Hatherill M(1), Davis MM(#)(2)(12)(13), Scriba TJ(#)(14); Adolescent Cohort

Study team; GC6-74 Consortium.

Author information:

(1)South African Tuberculosis Vaccine Initiative, Institute of Infectious

Disease and Molecular Medicine, and Division of Immunology, Department of

Pathology, University of Cape Town, Cape Town, South Africa.

(2)Institute for Immunity, Transplantation and Infection, Stanford University

School of Medicine, Stanford, CA, USA.

(3)Human Immune Monitoring Center, Stanford University, Stanford, CA, USA.

…

Antigen-specific, MHC-restricted αβ T cells are necessary for protective

immunity against Mycobacterium tuberculosis, but the ability to broadly study

these responses has been limited. In the present study, we used single-cell and

bulk T cell receptor (TCR) sequencing and the GLIPH2 algorithm to analyze M.

tuberculosis-specific sequences in two longitudinal cohorts, comprising 166

individuals with M. tuberculosis infection who progressed to either tuberculosis

(n = 48) or controlled infection (n = 118). We found 24 T cell groups with

similar TCR-β sequences, predicted by GLIPH2 to have common TCR specificities,

which were associated with control of infection (n = 17), and others that were

associated with progression to disease (n = 7). Using a genome-wide M.

tuberculosis antigen screen, we identified peptides targeted by T cell

similarity groups enriched either in controllers or in progressors. We propose

that antigens recognized by T cell similarity groups associated with control of

infection can be considered as high-priority targets for future vaccine

development.

© 2023. The Author(s).

DOI: 10.1038/s41591-022-02110-9

PMCID: PMC9873565

PMID: 36604540 [Indexed for MEDLINE]

4. Cancer Cell. 2023 Jan 9;41(1):88-105.e8. doi: 10.1016/j.ccell.2022.11.015. Epub 2022 Dec 15.

KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to

RTK-RAS inhibition.

Pan Y(1), Han H(1), Hu H(1), Wang H(2), Song Y(3), Hao Y(4), Tong X(2), Patel

AS(1), Misirlioglu S(1), Tang S(1), Huang HY(1), Geng K(1), Chen T(1), Karatza

A(1), Sherman F(1), Labbe KE(1), Yang F(1), Chafitz A(1), Peng C(1), Guo C(2),

Moreira AL(5), Velcheti V(1), Lau SCM(1), Sui P(2), Chen H(6), Diehl JA(7),

Rustgi AK(8), Bass AJ(8), Poirier JT(1), Zhang X(3), Ji H(9), Zhang H(10), Wong

KK(11).

Author information:

(1)Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY,

USA.

(2)State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and

Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy

of Sciences, Shanghai, China.

(3)State Key Laboratory of Genetic Engineering, School of Life Sciences,

Zhongshan Hospital, Fudan University, Shanghai, China.

…

Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer

with limited treatment options. KMT2D is one of the most frequently mutated

genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown.

Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d

deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases

activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through

reprogramming the chromatin landscape to repress the expression of protein

tyrosine phosphatases. These events provoke a robust elevation in the oncogenic

RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor

afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in

patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study

identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and

suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS

inhibition.

Copyright © 2022 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.ccell.2022.11.015

PMID: 36525973 [Indexed for MEDLINE]

5. Nat Commun. 2023 Jan 31;14(1):387. doi: 10.1038/s41467-023-35832-6.

Single-cell analysis reveals prognostic fibroblast subpopulations linked to

molecular and immunological subtypes of lung cancer.

Hanley CJ(1)(2), Waise S(#)(3), Ellis MJ(#)(3), Lopez MA(4), Pun WY(4), Taylor

J(4), Parker R(3), Kimbley LM(3), Chee SJ(3)(5), Shaw EC(4), West J(3)(6),

Alzetani A(7), Woo E(7), Ottensmeier CH(3)(8)(5), Rose-Zerilli MJJ(3)(6), Thomas

GJ(9)(10)(11).

Author information:

(1)School of Cancer Sciences, University of Southampton, Southampton, SO16 6YD,

UK. C.J.Hanley@soton.ac.uk.

(2)Cancer Research UK and NIHR Southampton Experimental Cancer Medicine Centre,

Southampton, SO16 6YD, UK. C.J.Hanley@soton.ac.uk.

(3)School of Cancer Sciences, University of Southampton, Southampton, SO16 6YD,

UK.

…

Fibroblasts are poorly characterised cells that variably impact tumour

progression. Here, we use single cell RNA-sequencing, multiplexed

immunohistochemistry and digital cytometry (CIBERSORTx) to identify and

characterise three major fibroblast subpopulations in human non-small cell lung

cancer: adventitial, alveolar and myofibroblasts. Alveolar and adventitial

fibroblasts (enriched in control tissue samples) localise to discrete spatial

niches in histologically normal lung tissue and indicate improved overall

survival rates when present in lung adenocarcinomas (LUAD). Trajectory inference

identifies three phases of control tissue fibroblast activation, leading to

myofibroblast enrichment in tumour samples: initial upregulation of inflammatory

cytokines, followed by stress-response signalling and ultimately increased

expression of fibrillar collagens. Myofibroblasts correlate with poor overall

survival rates in LUAD, associated with loss of epithelial differentiation, TP53

mutations, proximal molecular subtypes and myeloid cell recruitment. In squamous

carcinomas myofibroblasts were not prognostic despite being transcriptomically

equivalent. These findings have important implications for developing

fibroblast-targeting strategies for cancer therapy.

© 2023. The Author(s).

DOI: 10.1038/s41467-023-35832-6

PMCID: PMC9889778

PMID: 36720863 [Indexed for MEDLINE]

6. J Clin Oncol. 2023 Jan 31:JCO2202186. doi: 10.1200/JCO.22.02186. Online ahead of print.

Adjuvant Osimertinib for Resected EGFR-Mutated Stage IB-IIIA Non-Small-Cell Lung

Cancer: Updated Results From the Phase III Randomized ADAURA Trial.

Herbst RS(1), Wu YL(2), John T(3), Grohe C(4), Majem M(5), Wang J(6), Kato T(7),

Goldman JW(8), Laktionov K(9), Kim SW(10), Yu CJ(11)(12), Vu HV(13), Lu S(14),

Lee KY(15), Mukhametshina G(16), Akewanlop C(17), de Marinis F(18), Bonanno

L(19), Domine M(20), Shepherd FA(21), Urban D(22)(23), Huang X(24), Bolanos

A(25), Stachowiak M(26), Tsuboi M(27).

Author information:

(1)Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven,

CT.

(2)Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and

Guangdong Academy of Medical Sciences, Guangzhou, China.

(3)Department of Medical Oncology, Austin Health, Melbourne, Australia.

…

PURPOSE: The phase III ADAURA (ClinicalTrials.gov identifier: NCT02511106)

primary analysis demonstrated a clinically significant disease-free survival

(DFS) benefit with adjuvant osimertinib versus placebo in EGFR-mutated stage

IB-IIIA non-small-cell lung cancer (NSCLC) after complete tumor resection (DFS

hazard ratio [HR], 0.20 [99.12% CI, 0.14 to 0.30]; P < .001). We report an

updated exploratory analysis of final DFS data.

METHODS: Overall, 682 patients with stage IB-IIIA (American Joint Committee on

Cancer/Union for International Cancer Control, seventh edition) EGFR-mutated

(exon 19 deletion/L858R) NSCLC were randomly assigned 1:1 (stratified by stage,

mutational status, and race) to receive osimertinib 80 mg once-daily or placebo

for 3 years. The primary end point was DFS by investigator assessment in stage

II-IIIA disease analyzed by stratified log-rank test; following early reporting

of statistical significance in DFS, no further formal statistical testing was

planned. Secondary end points included DFS in stage IB-IIIA, overall survival,

and safety. Patterns of recurrence and CNS DFS were prespecified exploratory end

points.

RESULTS: At data cutoff (April 11, 2022), in stage II-IIIA disease, median

follow-up was 44.2 months (osimertinib) and 19.6 months (placebo); the DFS HR

was 0.23 (95% CI, 0.18 to 0.30); 4-year DFS rate was 70% (osimertinib) and 29%

(placebo). In the overall population, DFS HR was 0.27 (95% CI, 0.21 to 0.34);

4-year DFS rate was 73% (osimertinib) and 38% (placebo). Fewer patients treated

with osimertinib had local/regional and distant recurrence versus placebo. CNS

DFS HR in stage II-IIIA was 0.24 (95% CI, 0.14 to 0.42). The long-term safety

profile of osimertinib was consistent with the primary analysis.

CONCLUSION: These updated data demonstrate prolonged DFS benefit over placebo,

reduced risk of local and distant recurrence, improved CNS DFS, and a consistent

safety profile, supporting the efficacy of adjuvant osimertinib in resected

EGFR-mutated NSCLC.

DOI: 10.1200/JCO.22.02186

PMID: 36720083

7. Nat Commun. 2023 Jan 23;14(1):363. doi: 10.1038/s41467-023-35864-y.

The NFIB/CARM1 partnership is a driver in preclinical models of small cell lung

cancer.

Gao G(#)(1), Hausmann S(#)(2), Flores NM(2), Benitez AM(2), Shen J(1), Yang

X(2), Person MD(3), Gayatri S(1)(4), Cheng D(5), Lu Y(1), Liu B(1), Mazur PK(6),

Bedford MT(7).

Author information:

(1)Department of Epigenetics and Molecular Carcinogenesis, The University of

Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

(2)Department of Experimental Radiation Oncology, The University of Texas MD

Anderson Cancer Center, Houston, TX, 77030, USA.

(3)Center for Biomedical Research Support, The University of Texas at Austin,

Austin, TX, 78712, USA.

…

The coactivator associated arginine methyltransferase (CARM1) promotes

transcription, as its name implies. It does so by modifying histones and

chromatin bound proteins. We identified nuclear factor I B (NFIB) as a CARM1

substrate and show that this transcription factor utilizes CARM1 as a

coactivator. Biochemical studies reveal that tripartite motif 29 (TRIM29) is an

effector molecule for methylated NFIB. Importantly, NFIB harbors both oncogenic

and metastatic activities, and is often overexpressed in small cell lung cancer

(SCLC). Here, we explore the possibility that CARM1 methylation of NFIB is

important for its transforming activity. Using a SCLC mouse model, we show that

both CARM1 and the CARM1 methylation site on NFIB are critical for the rapid

onset of SCLC. Furthermore, CARM1 and methylated NFIB are responsible for

maintaining similar open chromatin states in tumors. Together, these findings

suggest that CARM1 might be a therapeutic target for SCLC.

© 2023. The Author(s).

DOI: 10.1038/s41467-023-35864-y

PMCID: PMC9870865

PMID: 36690626 [Indexed for MEDLINE]

8. J Clin Oncol. 2023 Jan 23:101200JCO2202823. doi: 10.1200/JCO.22.02823. Online

ahead of print.

Tarlatamab, a first-in-class DLL3-targeted bispecific T cell engager, in

recurrent small-cell lung cancer: an open-label, phase 1 study.

Paz-Ares L(1), Champiat S(2), Lai WV(3), Izumi H(4), Govindan R(5), Boyer M(6),

Hummel HD(7), Borghaei H(8), Johnson ML(9), Steeghs N(10), Blackhall F(11),

Dowlati A(12), Reguart N(13), Yoshida T(14), He K(15), Gadgeel SM(16), Felip

E(17), Zhang Y(18), Pati A(18), Minocha M(18), Mukherjee S(18), Goldrick A(18),

Nagorsen D(18), Sadraei NH(18), Owonikoko TK(19).

Author information:

(1)Hospital Universitario 12 de Octubre, CNIO-H120 Lung Cancer Unit, Ciberonc

and Universidad Complutense, Madrid, Spain.

(2)Gustave Roussy, Département d'Innovation Thérapeutique et d'Essais Précoces

(DITEP), F-94805, Villejuif, France.

(3)Thoracic Oncology Service, Department of Medicine, Division of Solid Tumor

Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

…

PURPOSE: Small cell lung cancer (SCLC) is an aggressive malignancy with limited

treatments. Delta-like ligand 3 (DLL3) is aberrantly expressed in most SCLC.

Tarlatamab (AMG 757), a bispecific T cell engager molecule, binds both DLL3 and

CD3 leading to T cell-mediated tumor lysis. Herein, we report phase 1 results of

tarlatamab in patients with SCLC.

PATIENTS AND METHODS: This study evaluated tarlatamab in patients with

relapsed/refractory SCLC. The primary endpoint was safety. Secondary endpoints

included antitumor activity by modified RECIST 1.1, overall survival (OS), and

pharmacokinetics.

RESULTS: By July 19, 2022, 107 patients received tarlatamab in dose exploration

(0.003 to 100 mg; n=73) and expansion (100 mg; n=34) cohorts. Median prior lines

of anticancer therapy were 2 (range, 1-6); 49.5% received anti-programmed

death-1/programmed death ligand-1 therapy. Any grade treatment-related adverse

events (TRAEs) occurred in 97 patients (90.7%); grade ≥ 3 in 33 patients

(30.8%). One patient (1%) had grade 5 pneumonitis. Cytokine release syndrome was

the most common TRAE, occurring in 56 patients (52%) including grade 3 in 1

patient (1%). Maximum tolerated dose was not reached. Objective response rate

(ORR) was 23.4% (95% CI: 15.7, 32.5) including 2 complete and 23 partial

responses. Median duration of response was 12.3 months (95% CI: 6.6, 14.9).

Disease control rate was 51.4% (95% CI: 41.5, 61.2). Median progression-free

survival and OS were 3.7 months (95% CI: 2.1, 5.4) and 13.2 months (95% CI:

10.5, to not reached), respectively. Exploratory analysis suggests that

selecting for increased DLL3 expression can result in increased clinical

benefit.

CONCLUSION: In patients with heavily pretreated SCLC, tarlatamab demonstrated

manageable safety with encouraging response durability. Further evaluation of

this promising molecule is ongoing.

DOI: 10.1200/JCO.22.02823

PMID: 36689692

9. Nat Commun. 2023 Jan 19;14(1):303. doi: 10.1038/s41467-023-35813-9.

Phylogeography and transmission of Mycobacterium tuberculosis spanning prisons

and surrounding communities in Paraguay.

Sanabria GE(#)(1), Sequera G(#)(2)(3), Aguirre S(3), Méndez J(4), Dos Santos

PCP(5), Gustafson NW(6), Godoy M(6), Ortiz A(4), Cespedes C(3), Martínez G(4),

García-Basteiro AL(2)(7)(8), Andrews JR(9), Croda J(10)(11)(12), Walter KS(13).

Author information:

(1)Instituto Regional de Investigación en Salud, Caaguazú, Paraguay.

lalyestigarr@gmail.com.

(2)Instituto de Salud Global de Barcelona (ISGLOBAL), Barcelona, Spain.

(3)Programa Nacional de Control de la Tuberculosis, Ministerio de Salud Pública

y Bienestar Social (MSPyBS), Asunción, Paraguay.

…

Recent rises in incident tuberculosis (TB) cases in Paraguay and the increasing

concentration of TB within prisons highlight the urgency of targeting strategies

to interrupt transmission and prevent new infections. However, whether specific

cities or carceral institutions play a disproportionate role in transmission

remains unknown. We conducted prospective genomic surveillance, sequencing

471 Mycobacterium tuberculosis complex genomes, from inside and outside prisons

in Paraguay's two largest urban areas, Asunción and Ciudad del Este, from 2016

to 2021. We found genomic evidence of frequent recent transmission within

prisons and transmission linkages spanning prisons and surrounding populations.

We identified a signal of frequent M. tuberculosis spread between urban areas

and marked recent population size expansion of the three largest genomic

transmission clusters. Together, our findings highlight the urgency of

strengthening TB control programs to reduce transmission risk within prisons in

Paraguay, where incidence was 70 times that outside prisons in 2021.

© 2023. The Author(s).

DOI: 10.1038/s41467-023-35813-9

PMCID: PMC9849832

PMID: 36658111 [Indexed for MEDLINE]

10. J Clin Oncol. 2023 Jan 9:JCO2201359. doi: 10.1200/JCO.22.01359. Online ahead of print.

High-Dose Once-Daily Thoracic Radiotherapy in Limited-Stage Small-Cell Lung

Cancer: CALGB 30610 (Alliance)/RTOG 0538.

Bogart J(1), Wang X(2), Masters G(3), Gao J(2), Komaki R(4), Gaspar LE(5)(6),

Heymach J(4), Bonner J(7), Kuzma C(8), Waqar S(9), Petty W(10), Stinchcombe

TE(11), Bradley JD(12), Vokes E(13).

Author information:

(1)State University of New York Upstate Medical University, New York, NY.

(2)Alliance Statistics and Data Management Center, Duke University, Durham, NC.

(3)Delaware/Christiana Care NCORP, Helen Graham Cancer Center, Newark, DE.

…

PURPOSE: Although level 1 evidence supports 45-Gy twice-daily radiotherapy as

standard for limited-stage small-cell lung cancer, most patients receive

higher-dose once-daily regimens in clinical practice. Whether increasing

radiotherapy dose improves outcomes remains to be prospectively demonstrated.

METHODS: This phase III trial, CALGB 30610/RTOG 0538 (ClinicalTrials.gov

identifier: NCT00632853), was conducted in two stages. In the first stage,

patients with limited-stage disease were randomly assigned to receive 45-Gy

twice-daily, 70-Gy once-daily, or 61.2-Gy concomitant-boost radiotherapy,

starting with either the first or second (of four total) chemotherapy cycles. In

the second stage, allocation to the 61.2-Gy arm was discontinued following

planned interim toxicity analysis, and the study continued with two remaining

arms. The primary end point was overall survival (OS) in the intention-to-treat

population.

RESULTS: Trial accrual opened on March 15, 2008, and closed on December 1, 2019.

All patients randomly assigned to 45-Gy twice-daily (n = 313) or 70-Gy

once-daily radiotherapy (n = 325) are included in this analysis. After a median

follow-up of 4.7 years, OS was not improved on the once-daily arm (hazard ratio

for death, 0.94; 95% CI, 0.76 to 1.17; P = .594). Median survival is 28.5 months

for twice-daily treatment, and 30.1 months for once-daily treatment, with 5-year

OS of 29% and 32%, respectively. Treatment was tolerable, and the frequency of

severe adverse events, including esophageal and pulmonary toxicity, was similar

on both arms.

CONCLUSION: Although 45-Gy twice-daily radiotherapy remains the standard of

care, this study provides the most robust information available to help guide

the choice of thoracic radiotherapy regimen for patients with limited-stage

small-cell lung cancer.

DOI: 10.1200/JCO.22.01359

PMID: 36623230

11. PLoS Med. 2023 Jan 3;20(1):e1004091. doi: 10.1371/journal.pmed.1004091.

eCollection 2023 Jan.

Improving cascade outcomes for active TB: A global systematic review and

meta-analysis of TB interventions.

Marley G(1)(2), Zou X(3), Nie J(4), Cheng W(5)(6), Xie Y(2), Liao H(2), Wang

Y(2), Tao Y(2), Tucker JD(2)(7), Sylvia S(2)(8), Chou R(9), Wu D(2)(7), Ong

J(10), Tang W(1)(2).

Author information:

(1)Dermatology Hospital of Southern Medical University, Guangzhou, China.

(2)University of North Carolina Project-China, Guangzhou, China.

(3)Global Health Research Center, Guangdong Provincial People's Hospital

(Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou,

China.

…

BACKGROUND: To inform policy and implementation that can enhance prevention and

improve tuberculosis (TB) care cascade outcomes, this review aimed to summarize

the impact of various interventions on care cascade outcomes for active TB.

METHODS AND FINDINGS: In this systematic review and meta-analysis, we retrieved

English articles with comparator arms (like randomized controlled trials (RCTs)

and before and after intervention studies) that evaluated TB interventions

published from January 1970 to September 30, 2022, from Embase, CINAHL, PubMed,

and the Cochrane library. Commentaries, qualitative studies, conference

abstracts, studies without standard of care comparator arms, and studies that

did not report quantitative results for TB care cascade outcomes were excluded.

Data from studies with similar comparator arms were pooled in a random effects

model, and outcomes were reported as odds ratio (OR) with 95% confidence

interval (CI) and number of studies (k). The quality of evidence was appraised

using GRADE, and the study was registered on PROSPERO (CRD42018103331). Of

21,548 deduplicated studies, 144 eligible studies were included. Of 144 studies,

128 were from low/middle-income countries, 84 were RCTs, and 25 integrated TB

and HIV care. Counselling and education was significantly associated with

testing (OR = 8.82, 95% CI:1.71 to 45.43; I2 = 99.9%, k = 7), diagnosis (OR =

1.44, 95% CI:1.08 to 1.92; I2 = 97.6%, k = 9), linkage to care (OR = 3.10, 95%

CI = 1.97 to 4.86; I2 = 0%, k = 1), cure (OR = 2.08, 95% CI:1.11 to 3.88; I2 =

76.7%, k = 4), treatment completion (OR = 1.48, 95% CI: 1.07 to 2.03; I2 =

73.1%, k = 8), and treatment success (OR = 3.24, 95% CI: 1.88 to 5.55; I2 =

75.9%, k = 5) outcomes compared to standard-of-care. Incentives, multisector

collaborations, and community-based interventions were associated with at least

three TB care cascade outcomes; digital interventions and mixed interventions

were associated with an increased likelihood of two cascade outcomes each. These

findings remained salient when studies were limited to RCTs only. Also, our

study does not cover the entire care cascade as we did not measure gaps in

pre-testing, pretreatment, and post-treatment outcomes (like loss to follow-up

and TB recurrence).

CONCLUSIONS: Among TB interventions, education and counseling, incentives,

community-based interventions, and mixed interventions were associated with

multiple active TB care cascade outcomes. However, cost-effectiveness and

local-setting contexts should be considered when choosing such strategies due to

their high heterogeneity.

Copyright: © 2023 Marley et al. This is an open access article distributed under

the terms of the Creative Commons Attribution License, which permits

unrestricted use, distribution, and reproduction in any medium, provided the

original author and source are credited.

DOI: 10.1371/journal.pmed.1004091

PMCID: PMC9847969

PMID: 36595536 [Indexed for MEDLINE]

12. Nat Commun. 2022 Dec 29;13(1):7974. doi: 10.1038/s41467-022-35730-3.

Dynamic (18)F-Pretomanid PET imaging in animal models of TB meningitis and human

studies.

Mota F(#)(1)(2)(3), Ruiz-Bedoya CA(#)(1)(2)(3), Tucker EW(#)(1)(2)(4), Holt

DP(#)(5), De Jesus P(1)(2)(3), Lodge MA(5), Erice C(1)(2)(4), Chen X(1)(2)(3),

Bahr M(1)(2)(3), Flavahan K(1)(2)(3), Kim J(1)(2)(4), Brosnan MK(5), Ordonez

AA(1)(2)(3), Peloquin CA(6), Dannals RF(5), Jain SK(7)(8)(9)(10).

Author information:

(1)Center for Infection and Inflammation Imaging Research, Johns Hopkins

University School of Medicine, Baltimore, MD, 21287, USA.

(2)Center for Tuberculosis Research, Johns Hopkins University School of

Medicine, Baltimore, MD, 21287, USA.

(3)Department of Pediatrics, Johns Hopkins University School of Medicine,

Baltimore, MD, 21287, USA.

…

Pretomanid is a nitroimidazole antimicrobial active against drug-resistant

Mycobacterium tuberculosis and approved in combination with bedaquiline and

linezolid (BPaL) to treat multidrug-resistant (MDR) pulmonary tuberculosis (TB).

However, the penetration of these antibiotics into the central nervous system

(CNS), and the efficacy of the BPaL regimen for TB meningitis, are not well

established. Importantly, there is a lack of efficacious treatments for TB

meningitis due to MDR strains, resulting in high mortality. We have developed

new methods to synthesize 18F-pretomanid (chemically identical to the

antibiotic) and performed cross-species positron emission tomography (PET)

imaging to noninvasively measure pretomanid concentration-time profiles. Dynamic

PET in mouse and rabbit models of TB meningitis demonstrates excellent CNS

penetration of pretomanid but cerebrospinal fluid (CSF) levels does not

correlate with those in the brain parenchyma. The bactericidal activity of the

BPaL regimen in the mouse model of TB meningitis is substantially inferior to

the standard TB regimen, likely due to restricted penetration of bedaquiline and

linezolid into the brain parenchyma. Finally, first-in-human dynamic

18F-pretomanid PET in six healthy volunteers demonstrates excellent CNS

penetration of pretomanid, with significantly higher levels in the brain

parenchyma than in CSF. These data have important implications for developing

new antibiotic treatments for TB meningitis.

© 2022. The Author(s).

DOI: 10.1038/s41467-022-35730-3

PMCID: PMC9800570

PMID: 36581633 [Indexed for MEDLINE]

13. Angew Chem Int Ed Engl. 2023 Jan 2;62(1):e202212514. doi:

10.1002/anie.202212514. Epub 2022 Nov 30.

Tunable Strategy for the Asymmetric Synthesis of Sulfoglycolipids from

Mycobacterium tuberculosis To Elucidate the Structure and Immunomodulatory

Property Relationships.

Mondal S(1), Tseng CJ(1), Tan JJ(2), Lin DY(1), Lin HY(2), Weng JH(2), Lin

CH(2)(3)(4), Mong KT(1).

Author information:

(1)Applied Chemistry Department, National Yang Ming Chiao Tung University

(Previously National Chiao Tung University), 1001, University Road, Hsinchu

City, Taiwan, R. O. C.

(2)Institute of Biological Chemistry, Academia Sinica, No.128, Academia Road

Section2, Nan-Kang, Taipei, 11529, Taiwan.

(3)Graduate Institute of Biotechnology and Biotechnology Center, National

Chung-Hsing University, Taichung, 40227, Taiwan.

(4)Department of Chemistry and Institute of Biochemical Sciences, National

Taiwan University, Taipei, 10617, Taiwan.

We developed a versatile asymmetric strategy to synthesize different classes of

sulfoglycolipids (SGLs) from Mycobacterium tuberculosis. The strategy features

the use of asymmetrically protected trehaloses, which were acquired from the

glycosylation of TMS α-glucosyl acceptors with benzylidene-protected

thioglucosyl donors. The positions of the protecting groups at the donors and

acceptors can be fine-tuned to obtain different protecting-group patterns, which

is crucial for regioselective acylation and sulfation. In addition, a

chemoenzymatic strategy was established to prepare the polymethylated fatty acid

building blocks. The strategy employs inexpensive lipase as a desymmetrization

agent in the preparation of the starting substrate and readily available chiral

oxazolidinone as a chirality-controlling agent in the construction of the

polymethylated fatty acids. A subsequent investigation on the immunomodulatory

properties of each class of SGLs showed how the structures of SGLs impact the

host innate immunity response.

© 2022 Wiley-VCH GmbH.

DOI: 10.1002/anie.202212514

PMID: 36349422 [Indexed for MEDLINE]

14. J Exp Med. 2023 Jan 2;220(1):e20220484. doi: 10.1084/jem.20220484. Epub 2022 Nov 3.

Inherited human ITK deficiency impairs IFN-γ immunity and underlies

tuberculosis.

Ogishi M(1)(2), Yang R(#)(1), Rodriguez R(#)(3)(4), Golec DP(#)(5), Martin

E(3)(4), Philippot Q(4)(6), Bohlen J(4)(6), Pelham SJ(1), Arias AA(1)(7)(8),

Khan T(9), Ata M(9), Al Ali F(9), Rozenberg F(10), Kong XF(1), Chrabieh M(4)(6),

Laine C(4)(6), Lei WT(1), Han JE(1), Seeleuthner Y(4)(6), Kaul Z(5), Jouanguy

E(1)(4)(6), Béziat V(4)(6), Youssefian L(11)(12), Vahidnezhad H(11)(12), Rao

VK(13), Neven B(14), Fieschi C(15)(16), Mansouri D(17), Shahrooei M(18), Pekcan

S(19), Alkan G(20), Emiroğlu M(20), Tokgöz H(21), Uitto J(11)(12), Hauck

F(3)(4)(22), Bustamante J(#)(1)(4)(6)(23), Abel L(#)(1)(4)(6), Keles S(#)(24),

Parvaneh N(#)(25)(26), Marr N(#)(9)(27), Schwartzberg PL(#)(5), Latour

S(#)(3)(4), Casanova JL(#)(1)(4)(6)(28)(29), Boisson-Dupuis S(#)(1)(4)(6).

Author information:

(1)St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller

Branch, Rockefeller University, New York, NY.

(2)The David Rockefeller Graduate Program, Rockefeller University, New York, NY.

(3)Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection,

INSERM UMR1163, Paris, France.

…

Inborn errors of IFN-γ immunity can underlie tuberculosis (TB). We report three

patients from two kindreds without EBV viremia or disease but with severe TB and

inherited complete ITK deficiency, a condition associated with severe EBV

disease that renders immunological studies challenging. They have CD4+ αβ T

lymphocytopenia with a concomitant expansion of CD4-CD8- double-negative (DN) 

αβ and Vδ2- γδ T lymphocytes, both displaying a unique CD38+CD45RA+T-bet+EOMES- phenotype. 

Itk-deficient mice recapitulated an expansion of the γδ T and DN αβ T lymphocyte populations 

in the thymus and spleen, respectively. Moreover, the patients' T lymphocytes secrete small amounts 

of IFN-γ in response to TCR crosslinking, mitogens, or forced synapse formation with autologous B

lymphocytes. Finally, the patients' total lymphocytes secrete small amounts of

IFN-γ, and CD4+, CD8+, DN αβ T, Vδ2+ γδ T, and MAIT cells display impaired IFN-γ production in 

response to BCG. Inherited ITK deficiency undermines the development and function of various 

IFN-γ-producing T cell subsets, thereby underlying TB.

© 2022 Ogishi et al.

DOI: 10.1084/jem.20220484

PMCID: PMC9641312

PMID: 36326697 [Indexed for MEDLINE]

15. J Clin Oncol. 2023 Jan 20;41(3):651-663. doi: 10.1200/JCO.22.00727. Epub 2022

Oct 7.

Toripalimab Plus Chemotherapy for Patients With Treatment-Naive Advanced

Non-Small-Cell Lung Cancer: A Multicenter Randomized Phase III Trial

(CHOICE-01).

Wang Z(1), Wu L(2), Li B(3), Cheng Y(4), Li X(5), Wang X(6), Han L(7), Wu X(8),

Fan Y(9), Yu Y(10), Lv D(11), Shi J(12), Huang J(13), Zhou S(14), Han B(15), Sun

G(16), Guo Q(17), Ji Y(18), Zhu X(19), Hu S(20), Zhang W(21), Wang Q(22), …

Author information:

(1)CAMS Key Laboratory of Translational Research on Lung Cancer, State Key

Laboratory of Molecular Oncology, Department of Medical Oncology, National

Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital,

Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing,

China.

(2)Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of

Medicine, Central South University, Changsha, China.

(3)Beijing Chest Hospital, Capital Medical University, Beijing, China.

…

PURPOSE: The CHOICE-01 study investigated the efficacy and safety of toripalimab

in combination with chemotherapy as a first-line treatment for advanced

non-small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Patients (N = 465) with treatment-naive, advanced NSCLC

without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240

mg (n = 309) or placebo (n = 156) once every 3 weeks in combination with

chemotherapy for 4-6 cycles, followed by the maintenance of toripalimab or

placebo once every 3 weeks plus standard care. Stratification factors included

programmed death ligand-1 expression status, histology, and smoking status. The

primary end point was progression-free survival (PFS) by investigator per RECIST

v1.1. Secondary end points included overall survival and safety.

RESULTS: At the final PFS analysis, PFS was significantly longer in the

toripalimab arm than in the placebo arm (median PFS, 8.4 v 5.6 months, hazard

ratio = 0.49; 95% CI, 0.39 to 0.61; two-sided P < .0001). At the interim OS

analysis, the toripalimab arm had a significantly longer OS than the placebo arm

(median OS not reached v 17.1 months, hazard ratio = 0.69; 95% CI, 0.53 to 0.92;

two-sided P = .0099). The incidence of grade ≥ 3 adverse events was similar

between the two arms. Treatment effects were similar regardless of programmed

death ligand-1 status. Genomic analysis using whole-exome sequencing from 394

available tumor samples revealed that patients with high tumor mutational burden

were associated with significantly better PFS in the toripalimab arm (median PFS

13.1 v 5.5 months, interaction P = .026). Notably, patients with mutations in

the focal adhesion-PI3K-Akt signaling pathway achieved significantly better PFS

and OS in the toripalimab arm (interaction P values ≤ .001).

CONCLUSION: Toripalimab plus chemotherapy significantly improves PFS and OS in

patients with treatment-naive advanced NSCLC while having a manageable safety

profile. Subgroup analysis showed the OS benefit was mainly driven by the

nonsquamous subpopulation.

DOI: 10.1200/JCO.22.00727

PMCID: PMC9870236

PMID: 36206498 [Indexed for MEDLINE]

16. J Clin Oncol. 2023 Jan 10;41(2):385-394. doi: 10.1200/JCO.22.00393. Epub 2022

Sep 19.

Selpercatinib in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer:

Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II

Trial.

Drilon A(1), Subbiah V(2), Gautschi O(3), Tomasini P(4), de Braud F(5), Solomon

BJ(6), Shao-Weng Tan D(7), Alonso G(8), Wolf J(9), Park K(10), Goto K(11),

Soldatenkova V(12), Szymczak S(13), Barker SS(12), Puri T(12), Bence Lin A(12),

Loong H(14), Besse B(15).

Author information:

(1)Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center, New

York, NY.

(2)The University of Texas MD Anderson Cancer Center, Houston, TX.

(3)University of Berne and Cantonal Hospital of Lucerne, Lucerne, Switzerland.

…

Comment in

    J Clin Oncol. 2023 Jan 10;41(2):410-412.

    Nat Rev Clin Oncol. 2022 Dec;19(12):747.

PURPOSE: Selpercatinib, a first-in-class, highly selective, and potent

CNS-active RET kinase inhibitor, is currently approved for the treatment of

patients with RET fusion-positive non-small-cell lung cancer (NSCLC). We provide

a registrational data set update in more than double (n = 316) of the original

reported population (n = 144) and better characterization of long-term efficacy

and safety.

METHODS: Patients were enrolled to LIBRETTO-001, a phase I/II, single-arm,

open-label study of selpercatinib in patients with RET-altered cancers. An

analysis of patients with RET fusion-positive NSCLC, including 69

treatment-naive and 247 with prior platinum-based chemotherapy, was performed.

The primary end point was objective response rate (ORR; RECIST v1.1, independent

review committee). Secondary end points included duration of response (DoR),

progression-free survival (PFS), overall survival, and safety.

RESULTS: In treatment-naive patients, the ORR was 84% (95% CI, 73 to 92); 6%

achieved complete responses (CRs). The median DoR was 20.2 months (95% CI, 13.0

to could not be evaluated); 40% of responses were ongoing at the data cutoff

(median follow-up of 20.3 months). The median PFS was 22.0 months; 35% of

patients were alive and progression-free at the data cutoff (median follow-up of

21.9 months). In platinum-based chemotherapy pretreated patients, the ORR was

61% (95% CI, 55 to 67); 7% achieved CRs. The median DoR was 28.6 months (95% CI,

20.4 to could not be evaluated); 49% of responses were ongoing (median follow-up

of 21.2 months). The median PFS was 24.9 months; 38% of patients were alive and

progression-free (median follow-up of 24.7 months). Of 26 patients with

measurable baseline CNS metastasis by the independent review committee, the

intracranial ORR was 85% (95% CI, 65 to 96); 27% were CRs. In the full safety

population (n = 796), the median treatment duration was 36.1 months. The safety

profile of selpercatinib was consistent with previous reports.

CONCLUSION: In a large cohort with extended follow-up, selpercatinib continued

to demonstrate durable and robust responses, including intracranial activity, in

previously treated and treatment-naive patients with RET fusion-positive NSCLC.

DOI: 10.1200/JCO.22.00393

PMCID: PMC9839260

PMID: 36122315 [Indexed for MEDLINE]

17. J Clin Oncol. 2023 Jan 10;41(2):373-384. doi: 10.1200/JCO.22.00096. Epub 2022

Sep 7.

Safety, Immunogenicity, and 1-Year Efficacy of Universal Cancer Peptide-Based

Vaccine in Patients With Refractory Advanced Non-Small-Cell Lung Cancer: A Phase

Ib/Phase IIa De-Escalation Study.

Adotévi O(1)(2), Vernerey D(2)(3), Jacoulet P(4), Meurisse A(3), Laheurte

C(2)(5), Almotlak H(1), Jacquin M(6), Kaulek V(4), Boullerot L(2)(5)(6), Malfroy

M(2), Orillard E(1)(4), Eberst G(2)(4), Lagrange A(7), Favier L(7), Gainet-Brun

M(4), Doucet L(8), Teixeira L(8), Ghrieb Z(9), Clairet AL(10), Guillaume Y(10),

Kroemer M(10), Hocquet D(11), Moltenis M(12), Limat S(2)(10), Quoix E(13),

Mascaux C(14), Debieuvre D(15), Fagnoni-Legat C(10), Borg C(1)(2)(6), Westeel

V(2)(4).

Author information:

(1)Department of Medical Oncology, University Hospital of Besançon, Besançon,

France.

(2)INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté,

Besançon, France.

(3)Department of Medical Oncology, Methodology and Quality of Life Unit in

Oncology, University Hospital of Besançon, Besançon, France.

…

PURPOSE: Universal cancer peptide-based vaccine (UCPVax) is a therapeutic

vaccine composed of two highly selected helper peptides to induce CD4+ T

helper-1 response directed against telomerase. This phase Ib/IIa trial was

designed to test the safety, immunogenicity, and efficacy of a three-dose

schedule in patients with metastatic non-small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Patients with refractory NSCLC were assigned to receive

three vaccination doses of UCPVax (0.25 mg, 0.5 mg, and 1 mg) using a

Bayesian-based phase Ib followed by phase IIa de-escalating design. The primary

end points were dose-limiting toxicity and immune response after three first

doses of vaccine. Secondary end points were overall survival (OS) and

progression-free survival at 1 year.

RESULTS: A total of 59 patients received UCPVax; 95% had three prior lines of

systemic therapy. No dose-limiting toxicity was observed in 15 patients treated

in phase Ib. The maximum tolerated dose was 1 mg. Fifty-one patients were

eligible for phase IIa. The third and sixth dose of UCPVax induced specific CD4+

T helper 1 response in 56% and 87.2% of patients, respectively, with no

difference between three dose levels. Twenty-one (39%) patients achieved disease

control (stable disease, n = 20; complete response, n = 1). The 1-year OS was

34.1% (95% CI, 23.1 to 50.4), and the median OS was 9.7 months, with no

significant difference between dose levels. The 1-year progression-free survival

and the median OS were 17.2% (95% CI, 7.8 to 38.3) and 11.6 months (95% CI, 9.7

to 16.7) in immune responders (P = .015) and 4.5% (95% CI, 0.7 to 30.8) and 5.6

months (95% CI, 2.5 to 10) in nonresponders (P = .005), respectively.

CONCLUSION: UCPVax was highly immunogenic and safe and provide interesting

1-year OS rate in heavily pretreated advanced NSCLC.

DOI: 10.1200/JCO.22.00096

PMID: 36070539 [Indexed for MEDLINE]

18. Am J Respir Crit Care Med. 2023 Jan 15;207(2):193-205. doi:

10.1164/rccm.202201-0144OC.

Forgiveness Is the Attribute of the Strong: Nonadherence and Regimen Shortening

in Drug-sensitive Tuberculosis.

Stagg HR(1), Thompson JA(2), Lipman MCI(3), Sloan DJ(4), Flook M(1), Fielding

KL(2)(5).

Author information:

(1)Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.

(2)Department of Infectious Disease Epidemiology, London School of Hygiene &

Tropical Medicine, London, United Kingdom.

(3)Division of Medicine, University College London, London, United Kingdom.

(4)School of Medicine, University of St. Andrews, St. Andrews, United Kingdom;

and.

(5)School of Public Health, University of the Witwatersrand, Johannesburg, South

Africa.

Comment in

    Am J Respir Crit Care Med. 2023 Jan 15;207(2):127-129.

Rationale: "Forgiveness" charts the ability of a drug or regimen to withstand

nonadherence without negative clinical consequences. Objectives: We aimed to

determine the influence of regimen length, regimen drugs, and dosing, and when

during treatment nonadherence occurs on the forgiveness of antituberculosis

regimens. Methods: Using data from three randomized controlled trials comparing

experimental 4-month regimens for drug-sensitive tuberculosis with the standard

6-month regimen, we used generalized linear models to examine how the risk of a

negative composite outcome changed as dose-taking decreased. The percentage of

doses taken and the absolute number of doses missed were calculated during the

intensive and continuation phases of treatment, and overall. A mediation

analysis was undertaken to determine how much the association between intensive

phase dose-taking and the negative composite outcome was mediated through

continuation phase dose-taking. Measurements and Main Results: Forgiveness of

the 4- and 6-month regimens did not differ for any treatment period.

Importantly, 4-month regimens were no less forgiving of small numbers of

absolute missed doses than the 6-month regimen (e.g., for 3-7 missed doses vs.

no missed doses [baseline], 6-month regimen adjusted risk ratio 1.65 [95%

confidence interval, 0.80-3.41] and 4-month regimens 1.80 [1.33-2.45]). No

4-month regimen was conclusively more forgiving than another. We found evidence

of mediation by continuation phase dose-taking on the intensive phase

dose-taking and negative composite outcome relationship. Conclusions: With the

current appetite for, and progress toward, shorter drug-sensitive tuberculosis

regimens worldwide, we offer reassurance that shorter regimens are not

necessarily less forgiving of nonadherence. Given the importance of continuation

phase adherence, patient support during this period should not be neglected.

DOI: 10.1164/rccm.202201-0144OC

PMCID: PMC9893326

PMID: 35952354 [Indexed for MEDLINE]

19. Autophagy. 2023 Jan;19(1):3-23. doi: 10.1080/15548627.2021.2021495. Epub 2022

Jan 9.

The exploitation of host autophagy and ubiquitin machinery by Mycobacterium

tuberculosis in shaping immune responses and host defense during infection.

Shariq M(1), Quadir N(1)(2), Alam A(1), Zarin S(1)(2), Sheikh JA(3), Sharma

N(1)(2), Samal J(1), Ahmad U(1), Kumari I(1), Hasnain SE(4)(5), Ehtesham NZ(1).

Author information:

(1)Inflammation Biology and Cell Signaling Laboratory, National Institute of

Pathology-ICMR, Ansari Nagar West, New Delhi, India.

(2)Department of Molecular Medicine, Jamia Hamdard-Institute of Molecular

Medicine, Jamia Hamdard, New Delhi, India.

(3)Department of Biotechnology, School of Chemical and Life Sciences, Jamia

Hamdard, New Delhi, India.

(4)Department of Biochemical Engineering and Biotechnology, Indian Institute of

Technology, Delhi (IIT-D), New Delhi, India.

(5)Department of Life Science, School of Basic Sciences and Research, Sharda

University, Greater Noida, India.

Intracellular pathogens have evolved various efficient molecular armaments to

subvert innate defenses. Cellular ubiquitination, a normal physiological process

to maintain homeostasis, is emerging one such exploited mechanism. Ubiquitin

(Ub), a small protein modifier, is conjugated to diverse protein substrates to

regulate many functions. Structurally diverse linkages of poly-Ub to target

proteins allow enormous functional diversity with specificity being governed by

evolutionarily conserved enzymes (E3-Ub ligases). The Ub-binding domain (UBD)

and LC3-interacting region (LIR) are critical features of

macroautophagy/autophagy receptors that recognize Ub-conjugated on protein

substrates. Emerging evidence suggests that E3-Ub ligases unexpectedly protect

against intracellular pathogens by tagging poly-Ub on their surfaces and

targeting them to phagophores. Two E3-Ub ligases, PRKN and SMURF1, provide

immunity against Mycobacterium tuberculosis (M. tb). Both enzymes conjugate K63

and K48-linked poly-Ub to M. tb for successful delivery to phagophores.

Intriguingly, M. tb exploits virulence factors to effectively dampen

host-directed autophagy utilizing diverse mechanisms. Autophagy receptors

contain LIR-motifs that interact with conserved Atg8-family proteins to modulate

phagophore biogenesis and fusion to the lysosome. Intracellular pathogens have

evolved a vast repertoire of virulence effectors to subdue host-immunity via

hijacking the host ubiquitination process. This review highlights the

xenophagy-mediated clearance of M. tb involving host E3-Ub ligases and

counter-strategy of autophagy inhibition by M. tb using virulence factors. The

role of Ub-binding receptors and their mode of autophagy regulation is also

explained. We also discuss the co-opting and utilization of the host Ub system

by M. tb for its survival and virulence.Abbreviations: APC: anaphase promoting

complex/cyclosome; ATG5: autophagy related 5; BCG: bacille Calmette-Guerin; C2:

Ca2+-binding motif; CALCOCO2: calcium binding and coiled-coil domain 2; CUE:

coupling of ubiquitin conjugation to ER degradation domains; DUB:

deubiquitinating enzyme; GABARAP: GABA type A receptor-associated protein; HECT:

homologous to the E6-AP carboxyl terminus; IBR: in-between-ring fingers; IFN:

interferon; IL1B: interleukin 1 beta; KEAP1: kelch like ECH associated protein

1; LAMP1: lysosomal associated membrane protein 1; LGALS: galectin; LIR:

LC3-interacting region; MAPK11/p38: mitogen-activated protein kinase 11;

MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP3K7/TAK1:

mitogen-activated protein kinase kinase kinase 7; MAPK8/JNK: mitogen-activated

protein kinase 8; MHC-II: major histocompatibility complex-II; MTOR: mechanistic

target of rapamycin kinase; NBR1: NBR1 autophagy cargo receptor; NFKB1/p50:

nuclear factor kappa B subunit 1; OPTN: optineurin; PB1: phox and bem 1; PE/PPE:

proline-glutamic acid/proline-proline-glutamic acid; PknG:

serine/threonine-protein kinase PknG; PRKN: parkin RBR E3 ubiquitin protein

ligase; RBR: RING-in between RING; RING: really interesting new gene; RNF166:

RING finger protein 166; ROS: reactive oxygen species; SMURF1: SMAD specific E3

ubiquitin protein ligase 1; SQSTM1: sequestosome 1; STING1: stimulator of

interferon response cGAMP interactor 1; TAX1BP1: Tax1 binding protein 1; TBK1:

TANK binding kinase 1; TNF: tumor necrosis factor; TRAF6: TNF receptor

associated factor 6; Ub: ubiquitin; UBA: ubiquitin-associated; UBAN:

ubiquitin-binding domain in ABIN proteins and NEMO; UBD: ubiquitin-binding

domain; UBL: ubiquitin-like; ULK1: unc-51 like autophagy activating kinase 1.

DOI: 10.1080/15548627.2021.2021495

PMCID: PMC9809970

PMID: 35000542 [Indexed for MEDLINE]