The cold immunological landscape of ATM-deficient cancers DOI Creative Commons
S. K. Sinha, Victor Ng,

Ardijana Novaj

и другие.

Journal for ImmunoTherapy of Cancer, Год журнала: 2025, Номер 13(5), С. e010548 - e010548

Опубликована: Май 1, 2025

Background Mutations in genes encoding DNA repair factors, which facilitate mismatch repair, homologous recombination, or polymerase functions, are known to enhance tumor immunogenicity. Ataxia telangiectasia mutated ( ATM ) is a central regulator of double-strand break and frequently affected by somatic germline mutations various cancer types, including breast, prostate, pancreatic, lung cancer. However, the consequences loss on immunogenicity poorly understood. Methods We generated isogenic ATM-null models using CRISPR murine triple-negative breast (4T1) colorectal (CT26) cell lines. inactivation was confirmed PCR western blot. Immune infiltrates were assessed flow cytometry immunohistochemistry both tumors human samples from cancers (via The Cancer Genome Atlas institutional cohorts). In vivo, impact growth response immune checkpoint blockade (anti-programmed death protein-1 (PD-1)) evaluated. Furthermore, we compared effects different DNA-damaging agents—including an ATR inhibitor (RP-3500), PARP (olaparib), topoisomerase II etoposide—on interferon-stimulated gene (ISG) expression modulation. Results find that—in contrast other defects —ATM deficiency (1) fails encourage effector infiltration into tumors, (2) does not enable recruitment via synthetic lethality strategies clinical trials, such as with inhibition. Assessing agents Atm null revealed differential activation type I interferon (IFN) signaling, etoposide, inhibitor, emerging strongest activator ISG under these conditions. Yet, PD-1-targeted bolster therapeutic activity etoposide -null syngeneic models, nor it modify microenvironment, suggesting that IFN signaling alone insufficient overcome immunosuppression immunologically cold neoplasms. Conclusions deficiency, while compromising enhancing sensitivity radiation inhibition, increase antigenicity Altogether, our results have important implications for design novel combination therapies highlight importance immunological defective repair.

Язык: Английский

Profile of Yosef Shiloh DOI Creative Commons

Jennifer Viegas

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(3)

Опубликована: Янв. 14, 2025

Collective cognition is often mentioned as one of the advantages group living. But which factors actually facilitate smarts? To answer this, we compared how individuals and groups either ants or people tackle an identical ...Biological ensembles use collective intelligence to challenges together, but suboptimal coordination can undermine effectiveness cognition. Testing whether exceeds that individual impractical since ...

Язык: Английский

Процитировано

0
The STING Signaling: A Novel Target for Central Nervous System Diseases DOI Creative Commons
Min Song,

Jianxun Ren,

Zhipeng Zhu

и другие.

Cellular and Molecular Neurobiology, Год журнала: 2025, Номер 45(1)

Опубликована: Апрель 7, 2025

The canonical cyclic GMP-AMP (cGAMP) synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway has been widely recognized as a crucial mediator inflammation in many diseases, including tumors, infections, and tissue damage. STING signaling can also be activated cGAS- or cGAMP-independent manner, although the specific mechanisms remain unclear. In-depth studies on structural molecular biology have led to development therapeutic strategies involving modulators their targeted delivery. These may effectively penetrate blood-brain barrier (BBB) target multiple central nervous system (CNS) diseases humans. In this review, we outline both non-canonical pathways activation describe general associations between activity CNS diseases. Finally, discuss prospects for delivery clinical application agonists inhibitors, highlighting novel

Язык: Английский

Процитировано

0
The cGAS-STING pathway in atherosclerosis DOI Creative Commons
Siyu Wang, Yushan Chen, Bo Jin

и другие.

Frontiers in Cardiovascular Medicine, Год журнала: 2025, Номер 12

Опубликована: Апрель 25, 2025

Atherosclerosis (AS), a chronic inflammatory disease, remains leading contributor to cardiovascular morbidity and mortality. Recent studies highlight the critical role of cGAS-STING pathway-a key innate immune signaling cascade-in driving AS progression. This pathway is activated by cytoplasmic DNA from damaged cells, thereby triggering inflammation accelerating plaque formation. While risk factors such as aging, obesity, smoking, hypertension, diabetes are known exacerbate AS, emerging evidence suggests that these may also enhance pathway, which amplifies responses. Targeting this offers promising therapeutic strategy reduce burden diseases (CVD). In review, we summarize mechanisms explore its in evaluate potential inhibitors future candidates. By integrating current knowledge, aim provide insights for developing novel treatments mitigate CVD burden.

Язык: Английский

Процитировано

0
ATM and p53 in aging and cancer: a double-edged sword in genomic integrity DOI
Surya Nath Pandey, Muhammad Afzal,

Jyoti Uikey

и другие.

Biogerontology, Год журнала: 2025, Номер 26(3)

Опубликована: Май 5, 2025

Язык: Английский

Процитировано

0
The cold immunological landscape of ATM-deficient cancers DOI Creative Commons
S. K. Sinha, Victor Ng,

Ardijana Novaj

и другие.

Journal for ImmunoTherapy of Cancer, Год журнала: 2025, Номер 13(5), С. e010548 - e010548

Опубликована: Май 1, 2025

Background Mutations in genes encoding DNA repair factors, which facilitate mismatch repair, homologous recombination, or polymerase functions, are known to enhance tumor immunogenicity. Ataxia telangiectasia mutated ( ATM ) is a central regulator of double-strand break and frequently affected by somatic germline mutations various cancer types, including breast, prostate, pancreatic, lung cancer. However, the consequences loss on immunogenicity poorly understood. Methods We generated isogenic ATM-null models using CRISPR murine triple-negative breast (4T1) colorectal (CT26) cell lines. inactivation was confirmed PCR western blot. Immune infiltrates were assessed flow cytometry immunohistochemistry both tumors human samples from cancers (via The Cancer Genome Atlas institutional cohorts). In vivo, impact growth response immune checkpoint blockade (anti-programmed death protein-1 (PD-1)) evaluated. Furthermore, we compared effects different DNA-damaging agents—including an ATR inhibitor (RP-3500), PARP (olaparib), topoisomerase II etoposide—on interferon-stimulated gene (ISG) expression modulation. Results find that—in contrast other defects —ATM deficiency (1) fails encourage effector infiltration into tumors, (2) does not enable recruitment via synthetic lethality strategies clinical trials, such as with inhibition. Assessing agents Atm null revealed differential activation type I interferon (IFN) signaling, etoposide, inhibitor, emerging strongest activator ISG under these conditions. Yet, PD-1-targeted bolster therapeutic activity etoposide -null syngeneic models, nor it modify microenvironment, suggesting that IFN signaling alone insufficient overcome immunosuppression immunologically cold neoplasms. Conclusions deficiency, while compromising enhancing sensitivity radiation inhibition, increase antigenicity Altogether, our results have important implications for design novel combination therapies highlight importance immunological defective repair.

Язык: Английский

Процитировано

0