SUMMARY
Treatment of cancer has been revolutionized by immune checkpoint blockade
therapies. Despite the high rate of response in advanced melanoma, the majority
of patients succumb to disease. To identify factors associated with success or
failure of checkpoint therapy, we profiled transcriptomes of 16,291 individual
immune cells from 48 tumor samples of melanoma patients treated with checkpoint
inhibitors. Two distinct states of CD8+ T cells were defined by
clustering, and associated with patient tumor regression or progression. A
single transcription factor, TCF7, was visualized within
CD8+ T cells in fixed tumor samples and predicted positive
clinical outcome in an independent cohort of checkpoint-treated patients. We
delineated the epigenetic landscape and clonality of these T cell states, and
demonstrated enhanced anti-tumor immunity by targeting novel combinations of
factors in exhausted cells. Our study of immune cell transcriptomes from tumors
demonstrates a strategy for identifying predictors, mechanisms and targets for
enhancing checkpoint immunotherapy.
Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.
In the version of this article initially published, the right two labels along the horizontal axis of Fig. 8c (IntA and IntG) were in the incorrect order. The correct order is IntG (middle right) and IntA (far right). The error has been corrected in the HTML and PDF versions of the article.
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