LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade

Yi Liu,Yang Shi,Brian Debo,Zhennan Shi,Wanqiang Sheng,Mingfeng Li

doi:10.1038/s41467-021-27179-7

Abstract

Exhausted CD8+ T cells are key targets of immune checkpoint blockade therapy and their ineffective reinvigoration limits the durable benefit in some cancer patients. Here, we demonstrate that histone demethylase LSD1 acts to enforce an epigenetic program in progenitor exhausted CD8+ T cells to antagonize the TCF1-mediated progenitor maintenance and to promote terminal differentiation. Consequently, genetic perturbation or small molecules targeting LSD1 increases the persistence of the progenitor exhausted CD8+ T cells, which provide a sustained source for the proliferative conversion to numerically larger terminally exhausted T cells with tumor-killing cytotoxicity, thereby leading to effective and durable responses to anti-PD1 therapy. Collectively, our findings provide important insights into epigenetic mechanisms that regulate T cell exhaustion and have important implications for durable immunotherapy.

Highlights

Exhausted CD8+ T cells are key targets of immune checkpoint blockade therapy and their ineffective reinvigoration limits the durable benefit in some cancer patients
We mainly focused on the immunogenic MC38 tumor model, and in some instances the TRAMP-C2 model, to elucidate the T-cell intrinsic role of LSD1 in antitumor T cell immunity
When LSD1 was depleted in T cells, we found the percentage of TCF1+PD-1 at an intermediate level (PD-1int) cells significantly increased while the percentage of TCF1-PD-1hi cells correspondingly decreased compared with their wildtype counterparts on both day 12 and 18 (Fig. 4d)

Summary

Introduction

Exhausted CD8+ T cells are key targets of immune checkpoint blockade therapy and their ineffective reinvigoration limits the durable benefit in some cancer patients. Since proliferation of the progenitor exhausted CD8+ T cells in response to TCR stimulation and PD-1 blockade progressively leads to their conversion to terminally exhausted phenotype[2], approaches to maintain or expand the progenitor subset of exhausted CD8+ T cells may help sustain anti-tumor response induced by anti-PD-1 therapy In support of this hypothesis, the duration of response in melanoma patients who respond to anti-PD-1 treatment is positively correlated with the frequency of progenitor exhausted CD8+ T cells[6]. In response to PD-1 blocking antibodies, the increased pool of progenitor exhausted CD8+ T cells caused by LSD1 inhibition provides a sustained source for the conversion to more differentiated T cells with stronger tumor-killing cytotoxicity, which enables a long-lasting response to anti-PD-1 treatment

Methods

Results

Conclusion