CD8 T Cell May Determine Patient Responses to Immune Checkpoint Inhibitors for Melanoma

Researchers from Massachusetts General Hospital and the Broad institute of MIT and Harvard recently identified specific states of cytotoxic CD8+ T cells that are associated with patient response to checkpoint immunotherapy for melanoma.

The findings, published in Cell, identified specific biomarker proteins associated with these cell states. The data could potentially assist researchers in understanding why checkpoint therapy is not equally effective in all patients and may enable the development of certain tests to determine which patients may respond better to the treatment.

“Checkpoint inhibition therapies have completely changed the way patients with metastatic melanoma are being treated clinically today, and since they were first approved in 2011 they have given new hope to patients who otherwise would have very poor prognosis—an average survival of under a year—and few therapeutic options,” said Nir Hacohen, PhD, cosenior author of the study and director of the Center for Cancer Immunology in the Massachusetts General Hospital Center for Cancer Research.

In order to identify factors associated with the success or failure of checkpoint therapy, researchers profiled transcriptomes of 16,291 individual immune cells from 48 tumor samples of patients with melanoma treated with checkpoint inhibitors. Profiling transcriptomes led to the discovery of 2 distinct states of CD8+ T cells defined by clustering and were therefore associated with patient tumor regression or progression.

One transcription factor, TCF7, was visualized within CD8+ T cells and predicted positive clinical outcome in an independent cohort of checkpoint-treated patients. “We also found that tumor-infiltrating CD8 T cells that do not express the genes CD39 and TIM3 were positive for TCF7 and play an important role in tumor eradication in response to anti-PD1 therapy in cellular studies,” said Moshe Sade-Feldman, PhD, co-lead author of the MGH Center for Cancer Research.

In a mouse model of melanoma, researchers tested the effects of blocking the action of either one or both of the genes and found that blocking both concurrently reduced tumor size and increased 40-day survival. Combining an inhibitor of CD39 with approved checkpoint inhibitors PD1 or PD1/CTLA4 tripled the percentage of animals surviving at 40 days post-treatment.

Overall, the study demonstrated a strategy for identifying predictors, mechanisms, and targets for enhancing checkpoint immunotherapy. “Our results suggest that increasing the ratio of stem-like-cell memory CD8 T cells to exhausted-like cells may help make checkpoint inhibitors and perhaps other immunotherapies more effective,” said Keren Yizhak, PhD, of the Broad Institute and co-lead author of the study.

Reference

Sade-Feldman M, Yizhak K, Bjorgaard S, et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. [published online November 1, 2018]. Cell. 2018; 175(5): 998-1013.