Eomes Impedes Durable Response to Tumor Immunotherapy by Inhibiting Stemness, Tissue Residency, and Promoting the Dysfunctional State of Intratumoral CD8+ T Cells

Abstract

Sustaining efficacious T cell-mediated antitumor immune responses in the tumor tissues is the key to the success of cancer immunotherapy. Current strategies leverage altering the signals T cells sense in the tumor microenvironment (TME). Checkpoint inhibitor-based approaches block inhibitory signals such as PD-1 whereas cytokine-based therapies increase the level of immune-stimulatory cytokines such as IL-2. Besides extrinsic signals, the genetic circuit within T cells also participates in determining the nature and trajectory of antitumor immune responses. Here, we showed that efficacy of the IL33-based tumor immunotherapy was greatly enhanced in mice with T cell-specific Eomes deficiency. Mechanistically, we demonstrated that Eomes deficient mice had diminished proportions of exhausted/dysfunctional CD8+ T cells but increased percentages of tissue resident and stem-like CD8+ T cells in the TME. In addition, the IFNγ+TCF1+ CD8+ T cell subset was markedly increased in the Eomes deficient mice. We further demonstrated that Eomes bound directly to the transcription regulatory regions of exhaustion and tissue residency genes. In contrast to its role in inhibiting T cell immune responses at the tumor site, Eomes promoted generation of central memory T cells in the peripheral lymphoid system and memory recall responses against tumor growth at a distal tissue site. Finally, we showed that Eomes deficiency in T cells also resulted in increased efficacy of PD-1-blockade tumor immunotherapy. In all, our study indicates that Eomes plays a critical role in restricting prolonged T cell-mediated antitumor immune responses in the TME whereas promoting adaptive immunity in peripheral lymphoid organs.

Macrophages and cancer stem cells: a malevolent alliance

“…IL-33 has many biological functions that are involved both in the regulation of adaptive immune responses (Schmitz et al 2005 ; Schiering et al 2014 ; Bonilla et al 2012 ) and in tissue repair (Miller et al 2008 ; Jones et al 2010 ; Li et al 2014 ). Its role in tumors is under debate; in fact, on the one hand IL-33 can promote T cell antitumor activity (Villarreal et al 2014 ; Gao et al 2015 ), on the other, its expression has been associated with metastasis in several cancer models (Jovanovic et al 2014 ; Gillibert-Duplantier et al 2012 ; Liu et al 2014 ) and, accordingly, it is under study as a therapeutic target (Sun et al 2021 ). Fang et al observed that the overexpression or administration of IL-33 enhanced the growth of colon cancer cells, the formation of cell spheres, and the expression of stem cell genes (NANOG, NOTCH3 and OCT3/4) via phosphorylation of JNK (Fang et al 2017 ).…”

Targeting metabotropic glutamate receptor 4 for cancer immunotherapy

“…However, the expression of IFN-γ was significantly up-regulated in CD4 + and CD8 + T cells in Grm4 −/− mice (fig. S7G), suggesting that GRM4 regulates the same sets of genes in the tumor tissues and secondary lymphoid system ( 14 ). There were no statistical differences in the percentages of GZB-producing NK and CD8 + T cells (fig.…”

The Half-Life-Extended IL21 can Be Combined With Multiple Checkpoint Inhibitors for Tumor Immunotherapy

“…Since the expression of immune checkpoint molecules characterizes T and NK cell exhaustion and may limit the efficacy of combination therapy ( Wherry, 2011 ; Wherry and Kurachi, 2015 ; Yang et al, 2020 ; Moesta et al, 2020 ; Bastid et al, 2015 ; Zhang et al, 2019 ; Sade-Feldman et al, 2019 ; Haas and Obenauf, 2019 ; Sun et al, 2021 ), we next looked at the expression of checkpoint molecules Tim-3, Lag-3, and CD39 by multi-color flow cytometry. The expression of all three inhibitory receptors was significantly enhanced on Foxp3 - CD4 + T cells, Tregs, CD8 + T cells, and NK cells after combination therapy ( Figures 4A–N ).…”

“…The strong stimulation provided by IL21 and PD-1 blockade on effector T cells may result in hyperactivation, a state that is characterized by the expression of multiple immune inhibitory receptors. These receptors prevent immune-mediated pathology, but limits the antitumor activity ( Alvarez-Fernández et al, 2016 ; Haas and Obenauf, 2019 ; Sade-Feldman et al, 2019 ; Sun et al, 2021 ). We showed that triple combination therapy with Tim-3 or Lag-3, and quadruple therapy, further increases the efficacy of double therapy.…”