Reprogramming Tumor-Infiltrating Exhausted CD8+ T Cells for Enhanced and Durable Antitumor Immunity

Tumor-infiltrating CD8+ T cells are pivotal effectors of antitumor immune response. However, under conditions of chronic antigen stimulation and persistent immunosuppressive cues within the tumor microenvironment, these cells progressively acquire a dysfunctional state termed T cell exhaustion. As a result, exhausted T cells (TEX) exhibit markedly reduced cytotoxicity and limited persistence, which collectively constrain their contribution to effective antitumor immunity. Therefore, therapeutic strategies that reinvigorate or reprogram exhausted tumor-infiltrating lymphocytes (TILs) are essential for achieving robust and durable antitumor immunity.

In my PhD research, I discovered that interleukin-10 (IL-10) signaling reprograms exhausted TILs into long-lived circulating memory T cells. IL-10 mobilizes exhausted CD8+ T cells from the tumor microenvironment into the bloodstream while simultaneously inducing epigenetic remodeling that reinstates a memory-associated transcriptional program, revealing an unrecognized differentiation trajectory. Remarkably, these recirculating T cells (TREX) maintain clonal continuity with intratumoral TEX yet acquire potent cytotoxicity against tumor cells, providing an easily accessible source of tumor-reactive T cells to enhance antitumor immunity. In addition, I engineered a tumor-targeted immunocytokine, anti-HER2-IL-4, by fusing interleukin-4 (IL-4) with an antibody specific for human epidermal growth factor receptor 2 (HER2). I further showed that anti-HER2-IL-4 induces strong, CD8+ T cell-dependent antitumor efficacy without eliciting systemic toxicity. Collectively, these studies integrate mechanistic dissection and cytokine engineering to modulate the effector function and memory differentiation of TILs, providing innovative strategies to enhance the efficacy and durability of cancer immunotherapy.