Analysis of cancer-related immune suppressor mechanisms in mice

Division Of Basic Sciences - Nci

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Abstract

This year placed a specific focus on innate immune cells in the liver and studied Mucosal-associated invariant T (MAIT) cells represent an abundant innate-like T cell subtype in the human liver. MAITs are assigned crucial roles in regulating immunity and inflammation, yet their role in liver cancer remains elusive. Here, we present a MAIT- centered profiling of hepatocellular carcinoma (HCC) using scRNA-seq, flow cytometry, and 37-plex co-detection by indexing (CODEX) imaging of paired patient samples. These analyses highlight the heterogeneity and dysfunctionality of MAITs in HCC and their defective capacity to infiltrate liver tumors. Novel machine learning tools were used to dissect the spatial cellular interaction network within the MAIT neighborhood. Co- localization in the adjacent liver and interaction between niche-occupying CSF1R+PD-L1+ tumor-associated macrophages and MAITs was identified as key regulatory element of MAIT dysfunction. Perturbation of this cell-cell interaction in ex vivo co-culture studies using patient samples and in murine models reinvigorated MAIT cell cytotoxicity. These studies suggest that aPD-1/aPD-L1 therapies target MAITs in HCC patients.