2025 Hot Topic in Basic & Translational Science: Small Cell Lung Cancer - ePosters-EP01.03: ATM inhibition plus radiation increases chemokine expression in small cell lung cancer and improves tumour T cell infiltration after anti-PDL1 checkpoint blockade.

EP01.03: ATM inhibition plus radiation increases chemokine expression in small cell lung cancer and improves tumour T cell infiltration after anti-PDL1 checkpoint blockade.

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The study explores the combined effects of ATM inhibition (ATMi) and ionizing radiation (IR) on enhancing chemokine and immune checkpoint expression in small-cell lung cancer (SCLC), a challenging neuroendocrine tumor with limited treatment options. Despite anti-PD-L1 (aPDL1) therapies improving survival rates, many patients do not respond, potentially due to insufficient T cell infiltration. The hypothesis suggests that combining ATMi with IR could improve T cell infiltration via activation of innate pathways like cGAS-STING, making tumors more immunogenic and improving aPDL1 outcomes.<br /><br />The research involved in vitro and in vivo experiments, including a CRISPR screen identifying ATM inhibition as a top candidate for improving immunogenicity via increased micronuclei formation and cGAS translocation in SBC5 cells. This combination treatment led to upregulation of chemokines like CCL5 and CXCL10, as well as enhanced expression of surface PDL1 in SCLC cell lines. However, in vivo studies using KP1 syngeneic mice showed that while ATMi combined with IR increased T cell infiltration, this did not translate into additional benefits when aPDL1 was also applied.<br /><br />The conclusions highlight that ATMi can effectively act as a radiosensitizer to control tumor growth, notably enhancing chemokine transcription and PDL1 expression. Despite these effects, adding immunotherapy did not offer further benefits, suggesting a PDL1-independent mechanism of immunosuppression. The study calls for further investigation into other immune checkpoint mechanisms and the role of the myeloid population in overcoming current limitations in treatment efficacy.

Asset Subtitle

Bell Wu

Keywords

ATM inhibition

ionizing radiation

small-cell lung cancer

immune checkpoint

chemokine expression

T cell infiltration

cGAS-STING pathway

CRISPR screen

micronuclei formation

PDL1 expression