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- W4385808610 abstract "Abstract Immune checkpoint blockade (ICB) has improved outcome for metastatic melanoma patients but not all benefit from treatment. Several immune- and tumor intrinsic features are associated with clinical response at baseline. However, we need to further understand the molecular changes occurring during development of ICB resistance. Here, we collected biopsies from a unique cohort of 44 melanoma patients after progression to anti-CTLA4 or anti-PD1 monotherapy. Genetic alterations of antigen presentation and interferon gamma signaling pathways were observed in approximately 25% of ICB resistant cases. Anti-CTLA4 resistant lesions had a sustained immune response, including immune-regulatory features, as suggested by multiplex spatial and TCR clonality analyses. One anti-PD1 resistant lesion harbored a distinct immune cell niche, however, anti-PD1 resistant tumors were generally immune poor with non-expanded TCR clones. Such immune poor microenvironments were associated with melanoma cells having a de-differentiated phenotype lacking expression of MHC-I molecules. In addition, anti-PD1 resistant tumors had reduced fractions of PD1+ CD8+ T cells as compared to ICB naïve metastases. Collectively, these data show the complexity of ICB resistance and highlight differences between anti-CTLA4 and anti-PD1 resistance that may underlie differential clinical outcomes of therapy sequence and combination." @default.
- W4385808610 created "2023-08-15" @default.
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- W4385808610 date "2023-08-14" @default.
- W4385808610 modified "2023-10-02" @default.
- W4385808610 title "Molecular patterns of resistance to immune checkpoint blockade in melanoma" @default.
- W4385808610 doi "https://doi.org/10.21203/rs.3.rs-3128187/v1" @default.
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