Checkpoint Blockade Immunotherapy Relies on T-bet but Not Eomes to Induce Effector Function in Tumor-Infiltrating CD8+ T Cells

Abstract

Coinhibitory receptor blockade is a promising strategy to boost T-cell immunity against a variety of human cancers. However, many patients still do not benefit from this treatment, and responders often experience immune-related toxicities. These issues highlight the need for advanced mechanistic understanding to improve patient outcomes and uncover clinically relevant biomarkers of treatment efficacy. However, the T cell-intrinsic signaling pathways engaged during checkpoint blockade treatment are not well defined, particularly for combination approaches. Using a murine model to study how effector CD8+ T-cell responses to tumors may be enhanced in a tolerizing environment, we identified a critical role for the T-box transcription factor T-bet. Combination blockade of CTLA-4, PD-1, and LAG-3 induced T-bet expression in responding tumor/self-reactive CD8+ T cells. Eradication of established leukemia using this immunotherapy regimen depended on T-bet induction, which was required for IFNγ production and cytotoxicity by tumor-infiltrating T cells, and for efficient trafficking to disseminated tumor sites. These data provide new insight into the success of checkpoint blockade for cancer immunotherapy, revealing T-bet as a key transcriptional regulator of tumor-reactive CD8+ T-cell effector differentiation under otherwise tolerizing conditions.

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

“…We speculate that mTOR activation leads to the expression of T-bet in DLN CTLs stimulated by FCCP together with PD-L1 blockade. T-bet is important for the antitumor function of CTLs as well as for the development of memory precursors, which potentially give rise to the sufficient numbers of terminally differentiated effector CTLs required for tumor regression (52,53). On the other hand, terminally differentiated CTLs, which strongly express Eomes, were tolerized by chronic antigen recognition (53,54).…”

Validation of Intratumoral T-bet+ Lymphoid Cells as Predictors of Disease-Free Survival in Breast Cancer

“…Similarly, in a murine model of lung adenocarcinoma, T-bet deficiency led to a marked induction of tumor load (25). More recently, T-bet has been shown to be required for promoting blockade-induced CD8 þ T-cell effector responses sufficient to eradicate disseminated leukemia in an animal model (26). Furthermore, high numbers of T-bet þ intratumoral lymphoid cells have been found to correlate with improved outcome in gastric cancer (27) and in high-grade cervical intraepithelial neoplasia (28).…”

Rescue of Tolerant CD8+ T Cells during Cancer Immunotherapy with IL2:Antibody Complexes

“…We previously reported that treatment with combination checkpoint blockade (anti-PD-1/CTLA-4/LAG-3) prevented T-cell deletion and promoted effector cytokine production during cancer immunotherapy (21, 23). Here, treatment with IL2c resulted in more than a 5-fold increase in transferred T-cell numbers at day 8 compared to checkpoint blockade treatment (Fig.…”

“…We previously identified the pro-apoptotic protein Bim (encoded by Bcl2l11 ) as necessary for T-cell deletion in Alb:Gag hosts (21, 23). Here, Bcl2l11 gene expression was observed in untreated T cells from the tolerizing environment, but was nearly undetectable following treatment with IL2c (Fig.…”