Activation of NKT Cells in an Anti-PD-1–Resistant Tumor Model Enhances Antitumor Immunity by Reinvigorating Exhausted CD8 T Cells

Abstract

PD-1-based cancer immunotherapy is a successful example of immune checkpoint blockade that provides long-term durable therapeutic effects in patients with cancer across a wide spectrum of cancer types. Accumulating evidence suggests that anti-PD-1 therapy enhances antitumor immunity by reversing the function of exhausted T cells in the tumor environment. However, the responsiveness rate of patients with cancer to anti-PD-1 therapy remains low, providing an urgent need for optimization and improvement. In this study, we designed an anti-PD-1-resistant mouse tumor model and showed that unresponsiveness to anti-PD-1 is associated with a gradual increase in CD8 T-cell exhaustion. We also found that invariant natural killer T cell stimulation by the synthetic ligand α-galactosylceramide (αGC) can enhance the antitumor effect in anti-PD-1-resistant tumors by restoring the effector function of tumor antigen-specific exhausted CD8 T cells. IL2 and IL12 were among the cytokines produced by αGC stimulation critical for reinvigorating exhausted CD8 T cells in tumor-bearing mice and patients with cancer. Furthermore, we observed a synergistic increase in the antitumor effect between αGC-loaded antigen-presenting cells and PD-1 blockade in a therapeutic murine tumor model. Our study suggests NKT cell stimulation as a promising therapeutic strategy for the treatment of patients with anti-PD-1-resistant cancer. These findings provide mechanistic insights into the application of NKT cell stimulation as a potent adjuvant for immunotherapy against advanced cancer. .

Cancer Stem Cell Marker DCLK1 Correlates with Tumorigenic Immune Infiltrates in the Colon and Gastric Adenocarcinoma Microenvironments

“…Additionally, it is widely reported that exhausted CD8+ T cells also express CD8A but lose the ability to eradicate the tumor cell [86,87]. This is hypothesized to be one significant reason why immune blockade increases the function of exhausted CD8+ T cells [88,89]. Taken together, our findings that DCLK1 is positively correlated with CD8+ T cells, combined with our findings that DSS in patients with low DCLK1 expression and high CD8+ T cells showed no significant difference compared with low DCLK1 expression and low CD8+ T cells, might indicate that DCLK1 can be used to predict the effect of immunotherapies aimed at restoring function in exhausted CD8 T cells.…”

Phase I Study of a B Cell-Based and Monocyte-Based Immunotherapeutic Vaccine, BVAC-C in Human Papillomavirus Type 16- or 18-Positive Recurrent Cervical Cancer

“…We previously reported that an invariant NKT cell ligand, α-galactosyl ceramide, loaded in a tumor antigen-expressing B cell-based and monocyte-based vaccine (BVAC) elicited diverse antitumor immune responses [14][15][16]. Furthermore, BVAC can overcome the immune-escaping mechanisms of cancer cells, such as MHC-I molecule loss and an exhaustion of immune effector cells in the tumor microenvironment [17,18].…”

Natural Killer T Cells (NKT cells) Functions in Malignancies

“…Bae et al, found that in an anti-PD-1-resistant tumor-bearing mice, type I NKT cells stimulated with the synthetic αGalCer can enhance the anti-tumor immunity by renovating the effector function of tumor exhausted CD8 T cells. They suggested that NKT cell stimulated with αGC-loaded APC as an effective therapeutic strategy for the treatment of anti-PD-1-resistant cancer patients [91]. Recently, using chimeric antigen receptors (CARs)-type I NKT cells in Preclinical studies have yielded promising result.…”