Abstract 2147: Radiosensitization via ATM inhibition in small cell lung cancer leads to increased immunogenicity and tumor infiltration
Bibliographic record
Abstract
Abstract Purpose: Small cell lung cancer (SCLC) is an aggressive form of lung cancer with a dismal survival. PD-1/PD-L1 inhibitors have improved survival outcomes, but many patients fail to respond possibly due to a lack of T cell infiltration. Ionizing radiation (IR) activates innate regulatory genes through micronuclei formation and cGAS-STING upregulation. A previous in vitro dropout CRISPR screen has identified ATM as a top-ranked determinant of radiosensitization in SCLC cell-lines. Evaluation of ATM inhibition (ATMi) in combination with IR increases tumour T cell immunogenicity through a cGAS-STING-mediated mechanism. Methods and Materials: We investigated the combination of ATMi (AZD1390) and IR in SCLC cell-lines SBC5 and SHP77, to determine the synergism of cGAS-STING activation via immunofluorescence. Chemokine and cytokine expression following combination treatment was probed by qPCR and surface expression of PDL1 and HLA class I was quantified through flow cytometry. In the SCLC syngeneic mice, we evaluated the efficacy and immune-sensitizing effects of a triple combination of ATMi, RT and anti-PDL1 (ATMi+IR+ICB). Results: ATMi plus IR (ATMi+IR) lead to a significant (p < 0.001) increase of micronuclei frequency and cGAS micronuclei translocation relative to RT alone. ATMi+IR also resulted in a significant increase in CCL5 and CXCL10 expression compared to IR alone in SBC5 (FC = 6 and 1.5, respectively) and SHP77 (FC = 1.5 and 2, respectively). This phenotype was partially abrogated in cGAS knockout in SBC5 and H1048 cell-lines. Surface PDL1 increased by a FC of 3 in H82 in ATMi+IR relative to IR, while no change in surface HLA was observed. Within the KP1 syngeneic SCLC murine model, ATMi+IR+ICB led to a significant increase (p-value < 0.001) in T cell (CD45+CD3+) infiltration at day 12 relative to ATMi+IR. Interestingly, ATMi+IR had no change in T cell infiltration relative to both IR alone and IR plus anti-PDL1. Although an increase in T cell infiltration was observed, there was no additional benefit in tumour control of ATMi+IR+ICB compared to ATMi+IR. Conclusions: In this study, we demonstrated pharmacological inhibition of ATM enhanced SCLC chemokine expression in a cGAS-STING-dependent manner. We further validated this phenotype in a syngeneic SCLC murine model. Despite this marked improvement in SCLC T cell infiltration no further benefits was observed. Further studies are required to understand this lack of benefit. Citation Format: Bell Wu, Xiaozhuo Ran, Mary Shi, Lifang Song, Vivek Philip, Ming-Sound Tsao, Benjamin Lok. Radiosensitization via ATM inhibition in small cell lung cancer leads to increased immunogenicity and tumor infiltration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2147.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".