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Trp53 Mutation-Mediated mTORC1 Inhibition and Inflammation Suppression Confer Resistance to Checkpoint Immunotherapy

ABSTRACT: p53 is a critical tumor suppressor gene that inhibits cancer development by regulating cell cycle arrest, apoptosis, DNA repair, and metabolism. However, recent studies examining TP53 mutations in cancer immunotherapy have yielded inconsistent results, likely due to differences in tumor mutational burden (TMB) and the context-dependent roles of specific p53 mutants. In this study, we assessed the function of G242V and S258I Trp53 mutations in MC38 cells in the context of immunotherapy by generating Trp53 deletion and observed significantly enhanced responses to anti-PD-1 therapy. We next characterized how the Trp53 deletion in MC38 tumor cells alters the immune response. To this end, we performed single-cell RNA and paired single-cell TCR sequencing (scRNAseq and scTCRseq) of anti-PD-1 treated Trp53CON and Trp53KO MC38 tumors on day 11 after tumor cells inoculation.

ORGANISM(S): Mus musculus

PROVIDER: GSE295668 | GEO | 2025/08/31

REPOSITORIES: GEO

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Project description:Targeting the PD-1/PD-L1 pathway has changed the landscape of cancer immunotherapy, revolutionizing the treatment of many cancers. Somatic tumor mutational burden (TMB) and T-cell–inflamed gene expression profile (GEP) are clinically validated pan-tumor genomic biomarkers that predict responsiveness to anti-PD-1/anti-PD-L1 monotherapy in a variety of tumor types. Here we analyze the association between these biomarkers and efficacy in 11 commonly used preclinical murine syngeneic models using a rodent surrogate antibody (muDX400) of pembrolizumab, a humanized monoclonal antibody against PD-1. Response to muDX400 treatment was broadly classified in these models into 3 categories: highly responsive, partially responsive, and intrinsically resistant to therapy. Molecular and cellular profiling validated differences in immune-cell infiltration and activation in the tumor microenvironment of muDX400 responsive tumors. Baseline and post-treatment genomic analysis showed an association between murine-GEP and TMB and response to muDX400 treatment. To better understand the limitations, predictive nature and role of these models in guiding treatment options at the bedside, we extended our analysis to investigate a canonical set of cancer and immune biology-related gene expression signatures, including signatures of angiogenesis, monocytic myeloid derived suppressor cell (mMDSC) and stromal/EMT/TGF-β biology previously shown to have potential negative impact on immunotherapy efficacy in the clinic. Finally, reverse translation studies were performed to evaluate the association between murine-GEP and preclinical efficacy with standard of care and anti-angiogenic combinations with muDX400 which show promising clinical activity. These efforts begin to elucidate which biological mechanisms can and cannot be appropriately and productively tested in these preclinical models to facilitate the development of rational orthogonal combination strategies with checkpoint blockade as well as the evaluation of underlying biological mechanisms associated with response in the clinic

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Trp53 Mutation-Mediated mTORC1 Inhibition and Inflammation Suppression Confer Resistance to Checkpoint Immunotherapy

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