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

Area of Science:

• Oncology
• Immunology
• Preclinical Research

Background:

• Small cell lung cancer (SCLC) exhibits diverse molecular subtypes with unique immune microenvironments, complicating treatment strategies.
• Preclinical models are limited in recapitulating SCLC's complex tumor-immune interactions across subtypes.
• Understanding subtype-specific immune responses is crucial for developing effective immunotherapies.

Purpose of the Study:

• To evaluate peripheral blood mononuclear cell (PBMC) humanized mice (hu-mice) as a platform for modeling SCLC subtype-specific immune contexts.
• To assess the therapeutic sensitivity of different SCLC molecular subtypes to a combination regimen of AZD1390 (ATM inhibitor), radiotherapy (RT), and durvalumab (aPDL1).

Main Methods:

• Engraftment of SCLC cell lines representing ASCL1, NEUROD1, POU2F3, and inflamed subtypes into PBMC hu-mice.
• Analysis of T cell infiltration, exhaustion markers (PD1, CD39, TOX), and chemokine expression (CCL5, CXCL10) in response to therapy.
• Evaluation of tumor control and immune cell populations in xenografts treated with monotherapy or combination therapy.

Main Results:

• SCLC-inflamed subtypes showed higher T cell infiltration, with CD8+ T cells rapidly developing exhaustion markers.
• Durvalumab monotherapy provided tumor control only in the inflamed SBC5 cell line.
• Combination therapy (AZD1390 + RT) sensitized non-responsive xenografts by upregulating chemokines and PDL1, leading to enrichment of tumor-reactive T cells with reduced exhaustion.

Conclusions:

• PBMC hu-mice effectively model SCLC immune contextures and subtype-specific responses.
• Combination therapy involving AZD1390 and RT can overcome resistance to aPDL1 immunotherapy in SCLC.
• This preclinical model can guide the development of combinatorial strategies for SCLC treatment.