Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma

Abstract

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.

An endogenous glucocorticoid-cytokine signaling circuit promotes CD8+T cell dysfunction in the tumor microenvironment

“…Glucocorticoids can be produced in the TME and combine with the immune suppressive cytokine IL-27 to form an immunoregulatory circuit that promotes gene programs associated with CD8 + T cell dysfunction. The relevance of glucocorticoid signaling pathways to human cancer is supported by our observation that increased steroidogenic capacity in the TME correlated with decreased survival and that high expression of the glucocorticoid + IL-27 signature in the CD8 + TILs of melanoma patients correlated with failure to respond to checkpoint blockade therapy (Sade-Feldman et al, 2018).…”

“…To examine the relevance of glucocorticoid + IL-27 signaling in human disease, we scored the glucocorticoid + IL-27 signature in the single-cell data of TILs from melanoma patients preand post-treatment with checkpoint blockade (Sade-Feldman et al, 2018). We found that the glucocorticoid + IL-27 signature scored highly in CD8 + TILs that also scored highly for the T cell dysfunction signature (Figure 5f, panels V and VI).…”

Metastatic melanoma

“…It was noted on pathology that 15% of nucleated cells in the periphery and 5% of cells in the center were CD8‐positive lymphocytes. Although the significance of this observation is unclear, preliminary data demonstrate better outcomes for patients who have increased CD8 infiltration of their melanoma …”

ROGUE: an entropy-based universal metric for assessing the purity of single cell population

“…The purity evaluation could therefore eliminate such misleading conclusions, potentially aiding our understanding of cellular function, state and behavior. While pioneering approaches such as silhouette 7 , DendroSplit 8 , and distance ratio 9 have been devoted to determining the optimal number of identified clusters by calculating the ratio of within-cluster to inter-cluster dissimilarity, they are not comparable among datasets and have poor interpretability of cluster purity. For example, an average silhouette value of 0.7 indicates a fairly strong consistency for a given cluster, but it is still unknown whether this cluster is a pure population or a mixture of similar subpopulations especially when frequent dropout events occur.…”