Search

CD8+T cells control tumors but inevitably become dysfunctional in the tumor microenvironment. Here, we show that sodium chloride (NaCl) counteracts T cell dysfunction to promote cancer regression. NaCl supplementation during CD8+T cell culture induced effector differentiation, IFN-γ production and cytotoxicity while maintaining the gene networks responsible for stem-like plasticity. Accordingly, adoptive transfer of tumor-specific T cells resulted in superior anti-tumor immunity in a humanized mouse model. In mice, a high-salt diet reduced the growth of experimental tumors in a CD8+T cell-dependent manner by inhibiting terminal differentiation and enhancing the effector potency of CD8+T cells. Mechanistically, NaCl enhanced glutamine consumption, which was critical for transcriptional, epigenetic and functional reprogramming. In humans, CD8+T cells undergoing antigen recognition in tumors and predicting favorable responses to checkpoint blockade immunotherapy resembled those induced by NaCl. Thus, NaCl metabolism is a regulator of CD8+T cell effector function, with potential implications for cancer immunotherapy.

Stem cells are maintained by transcriptional programs that promote self-renewal and repress differentiation. Here, we found that the transcription factor c-Myb was essential for generating and maintaining stem cells in the CD8+T cell memory compartment. Following viral infection, CD8+T cells lacking Mybunderwent terminal differentiation and generated fewer stem cell–like central memory cells than did Myb-sufficient T cells. c-Myb acted both as a transcriptional activator of Tcf7(which encodes the transcription factor Tcf1) to enhance memory development and as a repressor of Zeb2(which encodes the transcription factor Zeb2) to hinder effector differentiation. Domain-mutagenesis experiments revealed that the transactivation domain of c-Myb was necessary for restraining differentiation, whereas its negative regulatory domain was critical for cell survival. Myboverexpression enhanced CD8+T cell memory formation, polyfunctionality and recall responses that promoted curative antitumor immunity after adoptive transfer. These findings identify c-Myb as a pivotal regulator of CD8+T cell stemness and highlight its therapeutic potential.

T cell activation upon TCR signaling can lead to development of effector and memory cells. Roychoudhuri and colleagues show that the transcription factor BACH2 promotes memory CD8+T cell generation by blocking access to genomic regulatory sites recognized by AP-1.