Two chemotherapeutic agents expand stem-like CD62L⁺CD8⁺ T cells in antitumor immune responses

Recent findings reveal that the precursors of exhausted CD8⁺ T (CD8⁺ Tpex) cells possess stem-like signatures in tumor immunity, which originate from tumor draining lymph node (TdLN)-derived tumor-specific memory (CD8⁺ T_TSM) cells. Both of these T subsets can be collectively referred to as stem-like CD8⁺ T cells, which demonstrate robust self-renewal ability and can proliferate and differentiate into transitory effector-like exhausted T cells (Tex^int). There are reports that chemotherapeutic drugs can promote the antitumor immune responses of patients by increasing the number of CD8⁺ T cells; however, whether chemotherapeutic drugs increase these two stem-like CD8⁺ T cells remain further exploration.

Tpex cell-associated subpopulations in human colorectal tumors were analyzed by using single-cell sequencing data. CT26 and B16 tumor models of wild type and Eomes conditional knockout mice were constructed, and the changes of T_TSM, Tpex and Tex subsets in mice were dissected by flow cytometry after treatment with decitabine (DAC), doxorubicin (DOX) and 5-Fluorouracil (5-FU).

In this study, we demonstrated that DAC and 5-FU expanded CD8⁺ T_TSM cells in TdLNs. At the same time, we validated that DAC and 5-FU substantially promoted the expansion of CD62L⁺CD8⁺ Tpex cells and subsequently increased effector function of CX3CR1⁺ CD8⁺ Tex^int cells. In addition, the conditional knockout of transcription factor Eomes in CD8⁺ T cells partially eliminated DAC-amplified CD62L⁺ CD8⁺ Tpex cells, but had no effect on such CD8⁺ T subset expanded by 5-FU.

The present study demonstrated that both DAC and 5-FU promoted the differentiation of stem-like CD8⁺ T_TSM cells in TdLNs and significantly enhanced the differentiation and expansion of stem-like CD62L⁺ CD8⁺ Tpex and CX3CR1⁺ Tex^int cells in tumor microenvironment. The knockout of Eomes partially influenced the role of DAC in promoting the differentiation and expansion of stem-like CD8⁺ T cells.