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

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.

CHA1: A New Combinatorial Therapy That Reciprocally Regulates Wnt and JAK/STAT/Interferon Signaling to Re-program Breast Tumors and the Tumor-Resident Landscape

“…The lead compounds would be predicted to globally disrupt epigenetic status through histone modifications (37). Several studies have identified biologically diverse signals that nonetheless and surprisingly intersect epigenetic mechanisms through a viral mimicry response to generate interferon (38)(39)(40)(41)(42)(43)(44)(45)(46). The work described here in the context of these studies support and elaborate fundamental mechanisms and the growing role of epigenetic regulation and machinery in defining tumor immunity and improving ICIs efficacy (47)(48)(49).…”

“…A common feature of CHA1 and of the LSD1 inhibitor (133) is that both lead to increased tumor infiltration of CD8 + T-cells. While CD8 + T-cells might be recruited to the tumor-resident environment, exhausted T-cells would still define an immunosuppressive environment.…”

Epigenetic Modification of PD-1/PD-L1-Mediated Cancer Immunotherapy against Melanoma

“…Therefore, the way to improve these exhausted CD8+ cells is a highlighted target during immunotherapy. LSD1 is associated with these exhausted CD8+ T cells [20]. LSD1 increases exhausted CD8+ T cells, which determine the anti-tumor cytotoxic reaction during anti-PD1 therapy [20].…”

“…LSD1 is associated with these exhausted CD8+ T cells [20]. LSD1 increases exhausted CD8+ T cells, which determine the anti-tumor cytotoxic reaction during anti-PD1 therapy [20].…”

“…The tumor obtains advantages in development via epigenetic modification. In addition, these epigenetic changes in the tumor drive the escape phenomenon in anti-tumor immune responses [20,21]. However, there are a limited number of studies regarding the detailed molecular mechanisms of epigenetic changes in both host immunity and malignant melanoma.…”