The cold immunological landscape of ATM-deficient cancers Journal Article
| Authors: | Sinha, S.; Ng, V.; Novaj, A.; Zhu, Y.; Yazaki, S.; Pei, X.; Derakhshan, F.; Pareja, F.; Setton, J.; Naulin, F.; Beltrán-Visiedo, M.; Shin, E.; Longhini, A. L. F.; Gardner, R.; Ma, J.; Ma, K.; Roulston, A.; Morris, S.; Koehler, M.; Powell, S.; Rosen, E.; Galluzzi, L.; Reis-Filho, J.; Khan, A.; Riaz, N. |
| Article Title: | The cold immunological landscape of ATM-deficient cancers |
| Abstract: | Background Mutations in genes encoding DNA repair factors, which facilitate mismatch repair, homologous recombination, or DNA polymerase functions, are known to enhance tumor immunogenicity. Ataxia telangiectasia mutated (ATM) is a central regulator of DNA double-strand break repair and is frequently affected by somatic or germline mutations in various cancer types, including breast, prostate, pancreatic, and lung cancer. However, the consequences of ATM loss on tumor immunogenicity are poorly understood. Methods We generated isogenic ATM-null models using CRISPR in murine triple-negative breast (4T1) and colorectal (CT26) cancer cell lines. ATM inactivation was confirmed by PCR and western blot. Immune cell infiltrates were assessed by flow cytometry and immunohistochemistry in both murine tumors and human samples from breast and lung cancers (via The Cancer Genome Atlas and institutional cohorts). In vivo, the impact of ATM loss on tumor growth and response to immune checkpoint blockade (anti-programmed cell death protein-1 (PD-1)) was evaluated. Furthermore, we compared the effects of different DNA-damaging agents - including an ATR inhibitor (RP-3500), a PARP inhibitor (olaparib), and the topoisomerase II inhibitor etoposide - on interferon-stimulated gene (ISG) expression and immune modulation. Results We find that - in contrast to other DNA repair defects - ATM deficiency (1) fails to encourage immune effector cell infiltration into tumors, and (2) does not enable immune cell recruitment via synthetic lethality strategies in clinical trials, such as with ATR inhibition. Assessing various DNA-damaging agents in Atm null tumors revealed a differential activation of type I interferon (IFN) signaling, with etoposide, a topoisomerase II inhibitor, emerging as the strongest activator of ISG under these conditions. Yet, PD-1-targeted immune checkpoint blockade does not bolster the therapeutic activity of etoposide in Atm-null syngeneic tumor models, nor does it modify the tumor microenvironment, suggesting that type I IFN signaling alone is insufficient to overcome immunosuppression in immunologically cold ATM null neoplasms. Conclusions ATM deficiency, while compromising DNA repair and enhancing sensitivity to radiation and ATR inhibition, does not increase tumor antigenicity or immunogenicity. Altogether, our results have important implications for the design of novel combination therapies for ATM null tumors and highlight the importance of antigenicity in the immunological consequences of defective DNA repair. © Author(s) (or their employer(s)) 2025. |
| Keywords: | immunohistochemistry; controlled study; protein phosphorylation; gene mutation; human cell; genetics; nonhuman; flow cytometry; polymerase chain reaction; neoplasm; neoplasms; cd8+ t lymphocyte; cell proliferation; mouse; animal; animals; mice; cell viability; dna damage; dna repair; breast cancer; gene expression; cell infiltration; etoposide; animal experiment; animal model; body weight; lung cancer; cytotoxicity; immunofluorescence; cell line, tumor; immunoreactivity; brca1 protein; brca2 protein; immunology; tumor cell line; western blotting; immunoblotting; atm protein; natural killer cell; tumor growth; gamma interferon inducible protein 10; cd3+ t lymphocyte; immunocompetent cell; olaparib; anesthesia; programmed death 1 receptor; checkpoint kinase rad3; gyrase inhibitor; tumor microenvironment; isoflurane; beta1 interferon; immune checkpoint inhibitor; humans; human; female; article; rna sequencing; cell viability assay; ataxia telangiectasia mutated proteins; malignant neoplasm; 4t1 cell line; m2 macrophage; transcription intermediary factor 1 beta; m1 macrophage; atm protein, human; interferon signaling; camonsertib; ct26 cell line; type i interferon signaling; atm protein, mouse; ataxia telangiectasia mutated deficient cancers |
| Journal Title: | Journal for ImmunoTherapy of Cancer |
| Volume: | 13 |
| Issue: | 5 |
| ISSN: | 2051-1426 |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2025-05-01 |
| Start Page: | e010548 |
| Language: | English |
| DOI: | 10.1136/jitc-2024-010548 |
| PUBMED: | 40350205 |
| PROVIDER: | scopus |
| PMCID: | PMC12067784 |
| DOI/URL: | |
| Notes: | Article -- MSK corresponding author is Nadeem Riaz -- Source: Scopus |
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