Checkpoint molecules coordinately restrain hyperactivated effector T cells in the tumor microenvironment

Abstract

The immune checkpoint blockade (ICB) immunotherapy has prolonged overall survival for cancer patients but the response rates are low. The resistance to ICB is likely due to compensatory upregulation of additional immune inhibitory molecules. In this study, we first systematically examined Tim-3 expression in immune cells in mouse tumors and found that Tim-3 was specifically up-regulated in a large number of Treg, conventional CD4 + , CD8 + T cells, dendritic cell 1 (DC1), and macrophage 1 (M1) in the tumor microenvironment (TME). Interestingly, Tim-3 + T cells in the TME were phenotypically effector but not "exhausted" T cells because Tim-3 + PD-1 + CD8 + T cells had a higher number of mitochondria, greater levels of glycolysis, and higher tumorspecific cytolytic activities compared to Tim-3 − PD-1 − CD8 + T cells. The combination treatment with Tim-3 and PD-1 mAbs resulted in a synergistic antitumor activity but also increased the expression of Lag-3 and GITR in TIL, demonstrating cross-regulation between multiple checkpoint molecules. Furthermore, we found that the antitumor efficacy with triple combination of Tim-3, PD-1, and Lag3 mAbs was much greater than any two antibodies. Mechanistically, we demonstrated that simultaneous targeting of Tim-3, PD-1, and Lag-3 cooperatively increased the levels of granzyme B and tumor-specific cytolytic activities of CD8 + TIL. Our data indicate that multiple checkpoint molecules are coordinately upregulated to inhibit the function of hyperactivated T cells in the TME and requirement for the simultaneous blockade of PD-1, Tim-3 and Lag3 for cancer treatment.

Trial watch: STING agonists in cancer therapy

“…Accumulating preclinical evidence documents the relevance of STING signaling in malignant cells and innate immune effectors of the tumor microenvironment for the initiation of anticancer immunity. [69][70][71] Initially, it has been proposed that the engulfment of dying cancer cells by tumor-infiltrating CD8α + DCs would trigger STING signaling in the latter, culminating in the abundant secretion of type I IFN and consequent activation of autocrine and paracrine pathways supporting the crosspriming of tumor-specific CD8 + cytotoxic T lymphocytes (CTLs). [72][73][74][75][76][77][78][79] Consistent with this model, Sting1 −/mice are unable to mount efficient T cell immunity against syngeneic melanomas 57 and gliomas, 80 correlating with deficient type I IFN production.…”

The tumor immune microenvironmental analysis of 2,033 transcriptomes across 7 cancer types

“…4c). There are several immune checkpoint genes including VTCN1, VISTA, LAG3, IDO1, IDO2 and TIM3 [32][33][34] that are emerging in the development of immunotherapy, and we compared the expressions of these genes between the immune subtypes. The patterns of differences between expressions across 7 cancers were inconsistent.…”

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

“…Exhausted T cells are a type of hyper activated effector cells characterized by expression of co-inhibitory receptors including PD-1, Tim-3, and Lag-3 ( Fourcade et al, 2010 ; Sakuishi et al, 2010 ; Wherry, 2011 ; Gao et al, 2012 ; Yang et al, 2020 ). Eomes has been associated with T cell exhaustion state ( Doering et al, 2012 ; Paley et al, 2012 ; Li et al, 2018 ).…”