Tumor-Associated Monocytes Reprogram CD8+ T Cells into Central Memory-Like Cells with Potent Antitumor Effects

Abstract

CD8⁺ T cells are critical for host antitumor responses, whereas persistent antigenic stimulation and excessive inflammatory signals lead to T cell dysfunction or exhaustion. Increasing early memory T cells can improve T cell persistence and empower T cell-mediated tumor eradication, especially for adoptive cancer immunotherapy. Here, it is reported that tumor-associated monocytes (TAMos) are highly correlated with the accumulation of CD8⁺ memory T cells in human cancers. Further analysis identifies that TAMos selectively reprogram CD8⁺ T cells into T central memory-like (T_CM-like) cells with enhanced recall responses. L-NMMA, a pan nitric oxide synthase inhibitor, can mitigate TAMo-mediated inhibition of T cell proliferation without affecting T_CM-like cell generation. Moreover, the modified T cells by TAMo exposure and L-NMMA treatment exhibit long-term persistence and elicit superior antitumor effects in vivo. Mechanistically, the transmembrane protein CD300LG is involved in TAMo-mediated T_CM-like cell polarization in a cell-cell contact-dependent manner. Thus, the terminally differentiated TAMo subset (CD300LG^highACE^low) mainly contributes to T_CM-like cell development. Taken together, these findings establish the significance of TAMos in boosting T-cell antitumor immunity.

Keywords: CD300LG; T cell exhaustion; T central memory‐like cells; nitric oxide synthase; tumor‐associated monocytes (TAMos).