Abstract
Immune checkpoint therapy (ICT) results in durable responses in individuals with some cancers, but not all patients respond to treatment. ICT improves CD8+ cytotoxic T lymphocyte (CTL) function, but changes in tumor antigen-specific CTLs post-ICT that correlate with successful responses have not been well characterized. Here, we studied murine tumor models with dichotomous responses to ICT. We tracked tumor antigen-specific CTL frequencies and phenotype before and after ICT in responding and non-responding animals. Tumor antigen-specific CTLs increased within tumor and draining lymph nodes after ICT, and exhibited an effector memory-like phenotype, expressing IL-7R (CD127), KLRG1, T-bet, and granzyme B. Responding tumors exhibited higher infiltration of effector memory tumor antigen-specific CTLs, but lower frequencies of regulatory T cells compared to non-responders. Tumor antigen-specific CTLs persisted in responding animals and formed memory responses against tumor antigens. Our results suggest that increased effector memory tumor antigen-specific CTLs, in the presence of reduced immunosuppression within tumors is part of a successful ICT response. Temporal and nuanced analysis of T cell subsets provides a potential new source of immune based biomarkers for response to ICT.
Highlights
Cancer immunotherapies that block inhibitory checkpoint receptors on T cells, such as cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed death receptor 1 (PD-1), have resulted in remarkable, long-term tumor control in a subset of patients [1,2,3]
The number of CD8+Thy1.1+granzyme B (GrB)+ TILs were significantly higher in the Immune checkpoint therapy (ICT) treated group (P = 0.013), but this difference was not found in endogenous CD8+ T cell populations, suggesting that our ICT regime increased the cytotoxic function of HAspecific cytotoxic T lymphocyte (CTL)
To determine whether HA-specific CTLs acquired a treatment frequencies of effector memory (TEM) surface phenotype in these non-responding animals, we examined the expression profiles of CD127 and KLRG1 based on their median fluorescence intensity (MFI)
Summary
Cancer immunotherapies that block inhibitory checkpoint receptors on T cells, such as cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed death receptor 1 (PD-1), have resulted in remarkable, long-term tumor control in a subset of patients [1,2,3]. Current biomarkers include the expression of checkpoint inhibitory ligands such as PD-L1 [4], tumor mutation burden [5], gene expression profiles of the tumor microenvironment [6], and the extent of tumor infiltrating immune cells [7]. Each biomarker has its own strengths and limitations, but there is currently no accurate predictor of responsiveness to ICT across multiple cancers. Developing novel, complementary biomarkers associated with successful response to ICT will guide clinical decisions and help understand the underlying immune mechanisms of a successful anti-tumor immune response [8]
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