Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity

Abstract

The immune response plays an important role in staving off cancer; however, mechanisms of immunosuppression hinder productive anti-tumor immunity. T cell dysfunction or exhaustion in tumor-bearing hosts is one such mechanism. PD-1 has been identified as a marker of exhausted T cells in chronic disease states, and blockade of PD-1–PD-1L interactions has been shown to partially restore T cell function. We have found that T cell immunoglobulin mucin (Tim) 3 is expressed on CD8+ tumor-infiltrating lymphocytes (TILs) in mice bearing solid tumors. All Tim-3+ TILs coexpress PD-1, and Tim-3+PD-1+ TILs represent the predominant fraction of T cells infiltrating tumors. Tim-3+PD-1+ TILs exhibit the most severe exhausted phenotype as defined by failure to proliferate and produce IL-2, TNF, and IFN-γ. We further find that combined targeting of the Tim-3 and PD-1 pathways is more effective in controlling tumor growth than targeting either pathway alone.

Characterization of age‐associated exhausted CD8+ T cells defined by increased expression of Tim‐3 and PD‐1

“…To address the relationship between the exhaustion of T cells and aging more specifically, we examined the expression of Tim‐3, which, along with PD‐1, defines T‐cell exhaustion during chronic infection or in tumors (Jin et al ., 2010; Sakuishi et al ., 2010) but has never been studied in a model of aging. To this end, we tested its expression on splenic T cells in naïve B6 aged mice at various ages: aged (20‐month‐old), mid‐aged (10‐month‐old), and young (3‐month‐old) mice.…”

“…These data indicate that PD‐1‐expressing CD8 + T cells in aged mice exist in two different subsets that can be separated based on their Tim‐3 expression and that Tim‐3 + PD‐1 + cells may represent a differentiation status that is distinct from that of Tim‐3 − PD‐1 + cells. Notably, the effector/memory phenotype of Tim‐3 + cells in aging animals was similar to the phenotype of tumor‐infiltrating Tim‐3 + cells (Sakuishi et al ., 2010). …”

“…Tim‐3‐ and PD‐1‐expressing CD8 + T cells display more severe exhaustion in chronic infection and tumor models than Tim‐3 − PD‐1 + cells, as indicated by their failure to proliferate and produce effector cytokines (Jin et al ., 2010; Sakuishi et al ., 2010). To determine whether Tim‐3 + PD‐1 + CD8 + T cells in aged mice display functionally exhausted properties, the proliferative capacities of aged CD8 + T cells in the presence of TCR stimulation were analyzed.…”

“…As has previously been shown, Tim‐3‐ and PD‐1‐expressing exhausted CD8 + T cells in chronic viral infections and tumor microenvironments are dysfunctional, as indicated by their loss of IFN‐γ and TNF‐α (Barber et al ., 2006; Jin et al ., 2010; Sakuishi et al ., 2010). To investigate whether Tim‐3 + PD‐1 + CD8 + T cells from aged mice exhibited similar exhausted functions compared to those from chronically infected or tumor‐bearing mice, in terms of cytokine producing abilities, the protein (Figs 6A,B, and S3) and mRNA (Fig.…”

“…Tim‐3 is expressed on PD‐1 + CD8 + T cells, and co‐blockade of Tim‐3 and PD‐1 restores the functions of exhausted CD8 + T cells during LCMV infection (Jin et al ., 2010). Furthermore, Tim‐3 is also known to be expressed on the surface of CD8 + tumor‐infiltrating lymphocytes in tumor‐bearing mice (Sakuishi et al ., 2010), which suggests its potential as a therapeutic target in various diseases.…”