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Immune determinants of the association between tumor mutational burden and immunotherapy response across cancer types.

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journal contribution
posted on 09.06.2022, 10:26 authored by Neelam Sinha, Sanju Sinha, Cristina Valero, Alejandro A Schäffer, Kenneth Aldape, Kevin Litchfield, Timothy A Chan, Luc GT Morris, Eytan Ruppin
The FDA has recently approved a high tumor mutational burden (TMB-high) biomarker, defined by {greater than or equal to}10 mutations/Mb, for the treatment of solid tumors with pembrolizumab, an immune checkpoint inhibitor (ICI) that targets PD1. However, recent studies have shown that this TMB-high biomarker is only able to stratify ICI responders in a subset of cancer types, and the mechanisms underlying this observation have remained unknown. The tumor immune microenvironment (TME) may modulate the stratification power of TMB (termed TMB power), determining if it will be predictive of ICI response in a given cancer type. To systematically study this hypothesis, we inferred the levels of 31 immune-related factors characteristic of the TME of different cancer types in The Cancer Genome Atlas (TCGA). Integration of this information with TMB and response data of 2,277 patients treated with anti-PD1 identified key immune factors that determine TMB power across 14 different cancer types. We find that high levels of M1 macrophages and low resting dendritic cells in the TME characterized cancer types with high TMB power. A model based on these two immune factors strongly predicted TMB power in a given cancer type during cross-validation and testing (Spearman Rho=0.76 & 1, respectively). Using this model, we predicted the TMB power in nine additional cancer types, including rare cancers, for which TMB and ICI response data are not yet publicly available. Our analysis indicates that TMB-high may be highly predictive of ICI response in cervical squamous cell carcinoma, suggesting that such a study should be prioritized.


Crick (Grant ID: 10169, Grant title: Swanton FC001169)