SCLC humanized mice identify T cell infiltration phenotypes in response to combination immune-radiation therapies

Molecular small cell lung cancer (SCLC) subtypes (ASCL1, NEUROD1, POU2F3, and inflamed) display distinct immune contextures, but preclinical modeling remains limited. We evaluated peripheral blood mononuclear cell (PBMC) humanized mice (hu-mice) as a platform to capture subtype-specific tumor-immune interactions and therapeutic sensitivity to the triplet regimen: AZD1390 (ATM inhibitor), radiotherapy (RT), and durvalumab (aPDL1). SCLC cell lines representing all molecular subtypes were engrafted into hu-mice, and while T cell infiltration varied across subtypes, SCLC-inflamed cell lines exhibited the highest levels of infiltration. Infiltrating CD8 + T cells rapidly acquired exhaustion markers PD1, CD39, and TOX. Although aPDL1 monotherapy achieved tumor control only in the inflamed SBC5 cell line, combination AZD1390 and RT upregulated chemokine expression (CCL5 and CXCL10) and increased surface PDL1 to sensitize previously non-responsive xenografts in vivo . Responding xenografts showed enrichment of CD39 + CD103 + tumor-reactive T cells with reduced terminal exhaustion (TCF1 − TOX + ). Overall, PBMC hu-mice may effectively recapitulate SCLC immune contextures and guide development of combinatorial strategies to overcome aPDL1 resistance.