Reverse Translating Molecular Determinants of Anti-Programmed Death 1 Immunotherapy Response in Mouse Syngeneic Tumor...

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• The programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway is a key target in cancer immunotherapy.
• Somatic tumor mutational burden (TMB) and T-cell-inflamed gene expression profile (GEP) are established biomarkers for predicting response to anti-PD-1/PD-L1 therapy.

Purpose of the Study:

• To assess the association between TMB, murine-GEP, and the efficacy of PD-1 inhibition in preclinical syngeneic mouse models.
• To explore underlying biological mechanisms of response and resistance to PD-1 blockade.
• To evaluate combination strategies involving PD-1 inhibition with chemotherapy or antiangiogenic agents.

Main Methods:

• Utilized 11 preclinical syngeneic mouse tumor models treated with a murinized anti-PD-1 antibody (muDX400).
• Classified treatment response into highly responsive, partially responsive, and intrinsically resistant categories.
• Performed molecular and cellular profiling, including genomic analysis of TMB and murine-GEP, and assessed gene signatures related to angiogenesis, myeloid-derived suppressor cells, and TGFβ biology.

Main Results:

• Demonstrated a correlation between baseline TMB, murine-GEP, and response to muDX400 treatment.
• Identified distinct immune cell infiltration and activation patterns in responsive versus resistant tumors.
• Showed that murine-GEP can predict efficacy of combination therapies with chemotherapy or antiangiogenic agents.

Conclusions:

• Preclinical models confirm TMB and murine-GEP as predictive biomarkers for PD-1 blockade efficacy.
• Genomic and immune profiling provides insights into mechanisms of response and resistance.
• Findings support the use of these models for evaluating novel combination immunotherapies.