Abstract LB100: Understanding how IL-2 cytokine synergizes with PD-1 therapy during chronic viral infection

Abstract

Abstract In this study we have examined how the cytokine interleukin-2 (IL-2) synergizes with programmed cell death-1 (PD-1) directed immunotherapy during chronic lymphocytic choriomeningitis virus (LCMV) infection. PD-1 blockade in combination with IL-2 is one of the most effective combination therapies in this very stringent LCMV mouse model of life-long chronic infection with irreversible T-cell exhaustion. Our paper makes the following points: First, we show that the more effective viral control seen after PD-1 + IL-2 combination therapy compared to PD-1 monotherapy is mediated by the CD8+ T-cell response. Then we identify the virus-specific CD8+ T cells that proliferate and respond to the combination therapy and show that these are the same lymphoid resident PD-1+ TCF-1+ stem-like CD8+ T cells that act as resource cells to maintain the CD8+ T-cell response during chronic infection and also respond to PD-1 blockade. However, the combination therapy dramatically changes the differentiation program of these chronic resource CD8+ T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8+ T cells that resemble highly functional effector CD8+ T cells seen after an acute viral infection. In contrast, PD-1 monotherapy does not modify the differentiation program and one gets more virus-specific CD8+ T cells but they are transcriptionally and epigenetically similar to what is seen in untreated chronically infected mice. This epigenetic inflexibility of exhausted CD8+ T cells is a potential barrier to PD-1 therapy and the ability of this combination therapy to modify the epigenetic signature of virus-specific CD8+ T cells during chronic infection could be an important determinant of the striking synergy seen between IL-2 therapy and PD-1 blockade. We also highlight the importance of blocking the PD-1/PD-L1 inhibitory pathway at the target site for effective viral control. Expanding the CD8+ T cell population and generating better effector cells is important but it is also critical to block PD-1 inhibitory signals at the target site for optimal immunotherapy. Finally, we show that CD25 engagement with IL-2 plays an important and essential role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind CD25 but still binds CD122/132 almost completely abrogated the synergistic effects seen after PD-1/IL-2 combination therapy. There is currently considerable interest in PD-1 + IL-2 combination therapy for cancer patients and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies. Citation Format: Masao Hashimoto. Understanding how IL-2 cytokine synergizes with PD-1 therapy during chronic viral infection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB100.