The study findings suggest that there might exist “a happy medium, where classically defined ‘exhausted/dysfunctional’ cells are in reality mediating the majority of the response,” Reiser said. “It may be that these cells are the most amenable to immunotherapies.”

The frequency of tumor-infiltrating CD8+ T cells has been found to be associated with cancer-free survival time among patients with melanoma and several other solid tumor types. Immune checkpoint inhibition enhances these cells’ antitumor response.3

Treatment-naive T cells either transitioned toward a dysfunctional but still-proliferative state or became bystander cytotoxic cells.1 Dynamics in the separate pool of bystander cytotoxic T cells in the melanoma microenvironment was not linked to trends in the dysfunctional CD8+ T cell population, the study authors noted.

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“It will be interesting to determine which factors in human tumors drive the separate formation of the transitional-dysfunctional axis on the one hand, and the cytotoxic T cell pool on the other hand,” the researchers reported.1 “As a first possibility, the cell populations that together form the observed differentiation trajectory may be undergoing antigen recognition at the tumor site, thereby potentially driving — together with intratumoral factors — both the proliferation and the differentiation process that is observed.”

Alternatively, the distinct T cell pools might each separately be tumor reactive, they noted.1 More data are needed to determine which is the case, the authors cautioned. 

Disclosures: The study was funded by Merck KGaA, in Darmstadt, Germany. Please refer to reference for a complete list of authors’ disclosures.


  1. Li H, van der Leun AM, Yofe I, et al. Dysfunctional CD8 T cells for a proliferative, dynamically regulated compartment within human melanoma. Cell. 2019;176:775-789.e18. doi: 10.1016/j.cell.2018.11.043