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

Introduction:

Treatment of advanced melanoma patients with checkpoint blockade (CPB) therapies leads to longer survival and more durable responses in 15-40% of patients. Despite this major advance, the majority of patients are still not responding to these therapies, and 40-70% of responders relapse in 8-14 months.

Methods:

To identify key immunological components associated with success or failure of immunotherapy, we profiled 16,291 immune cells from 48 tumor samples of melanoma patients treated with checkpoint inhibitors, using single-cell transcriptomics. In addition, we performed functional studies of new therapeutic combination that enhanced immunity in a mouse melanoma model.

Results:

We identified unique exhaustion and memory/effector states of CD8⁺ T-cells associated with tumor regression, and found that the expression of a single transcription factor, TCF7, in CD8⁺ T-cells was sufficient to predict clinical outcome in an independent cohort, as determined by a simple immunofluorescence staining assay followed by automated image analysis. In addition, we delineated the epigenetic landscape and clonality of these T-cell states, and demonstrated enhanced anti-tumor immunity by targeting a novel combination of factors identified in exhausted cells.

Conclusions:

Our study provides extensive unbiased data in human tumors for discovery of predictors, therapeutic targets and combination therapies for enhancing checkpoint immunotherapy.