Abstract Background: Molecular classification of SCLC into subtypes (SCLC-ASCL1, SCLC-NEUROD1, SCLC-POU2F3, and SCLC-Inflamed) has revealed distinct immune contextures; however, preclinical research of the tumor-immune microenvironment is constrained by limited models that poorly capture POU2F3 and inflamed subtypes. To address this, we investigated peripheral blood mononuclear cell (PBMC) humanized mice (hu-mice) as a complement to conventional murine systems to broaden available tumor-immune models. We further characterized SCLC hu-mice for their ability to model therapeutic sensitivity, focusing on a novel triplet regimen, AZD1390 (ATM inhibitor) with radiotherapy (RT) and durvalumab (aPDL1), to investigate how DNA damage repair inhibition plus RT can reshape the immune microenvironment and sensitize SCLC subtypes to aPDL1. Methods: Immunodeficient mice were intravenously injected with human PBMCs and subcutaneously engrafted with a panel of human SCLC cell-lines corresponding to all subtypes. Peripheral and infiltrating immunity were profiled with multiparameter flow cytometry to assess cytokine, exhaustion, and activation of subtype-specific tumour-immune interactions. Tumor infiltration kinetics and antitumor effects were evaluated following durvalumab monotherapy and combination therapy. Results: T cell tumor infiltration varied by subtype with SCLC-Inflamed subtypes exhibiting the highest level of infiltration in an HLA-independent fashion. Infiltrating CD8+ T cells rapidly acquired an exhaustion phenotype upregulating PD1, CD39, TOX and downregulating Ki67, IFNG, and TCF1, consistent with impaired effector function. aPDL1 monotherapy revealed subtype-specific sensitivity of engrafted cell-lines, with tumour control across multiple donors seen only in the SCLC-Inflamed cell-line, SBC5. AZD1390 and RT was selected as a candidate combination with aPDL1 as it stimulated increased chemokine (CCL5, CXCL10) expression via a cGAS-STING-mediated mechanism and increased surface PDL1 expression across multiple cell-lines in vitro. AZD1390 and RT sensitized otherwise non-responsive xenografts to aPDL1 in vivo. Treatment response was associated with higher proportions of CD39+CD103+ tumor-reactive T cells and reduced terminal exhaustion (TCF1-TOX+) suggesting a shift towards a more functional T cell repertoire. Conclusions: Our preclinical observations demonstrate PBMC hu-mice as a viable platform to model intrinsic immune-tumor characteristics of engrafted human SCLC cell-lines. Combinatory radiation therapy enhanced anti-PDL1 efficacy in select models. Future studies will aim to identify response-defining features of treated models to improve patient selection in clinical trials. Citation Format: Bell Wu, Xiaozhuo Ran, Olivia Huang, Lifang Song, Vivek Phillip, Adrian Sacher, Ming Sound Tsao, Benjamin Lok. Small cell lung cancer humanized mouse models identifies unique T cell infiltration immune phenotypes in response to combination immune-radiation therapies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3379.
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