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PD-1+TCF-1+ stem-like CD8 T cells differentiate into effector T cells with enhanced anti-tumor and viral efficacy upon PD-1 cis-targeted IL-2R-agonism”

ABSTRACT: Here we show that IL-2Rbg-biased agonists are unable to preferentially expand better effector T cells in cancer models, and describe PD1-IL2v, a novel immunocytokine, that overcomes the need for CD25 binding by docking in cis to PD-1. In cis binding of PD1-IL2v to PD-1 and IL-2Rbg on the same cell recovers the ability to differentiate stem-like CD8 T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models, and provides superior efficacy.

ORGANISM(S): Mus musculus

PROVIDER: GSE208556 | GEO | 2022/07/21

REPOSITORIES: GEO

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Project description: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 doesnot 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+ Tcell 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.

Dataset Information

PD-1+TCF-1+ stem-like CD8 T cells differentiate into effector T cells with enhanced anti-tumor and viral efficacy upon PD-1 cis-targeted IL-2R-agonism”

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