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Therapeutic modulation of NKG7 in CD8+ T cells increases anti-tumor cytotoxicity and improves response to immune checkpoint inhibitors

ABSTRACT: Monoclonal antibodies that block PD-1/PD-L1 inhibitory signaling have been successfully used to treat a variety of solid tumor malignancies, but only a subset of patients benefit from this treatment. It remains unclear why the majority of patients fail to respond and what other limiting factors are at play. Here we show that natural killer cell granule protein-7 (NKG7) is critical for the anti-tumor activity of CD8+ T cells and response to anti-PD-1 therapy. We performed single-cell RNA sequencing analysis of peripheral CD8+ T cells from patients treated with anti-PD-1 and found that NKG7 gene expression was decreased in the non-responding patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164237 | GEO | 2022/02/18

REPOSITORIES: GEO

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Project description:Hepatocellular carcinoma (HCC) has dismal treatment responses to systemic therapies and is caused by both, viral and non-viral etiologies, including non-alcoholic steatohepatitis (NASH) 1–5. NASH - triggered by high caloric intake and sedentary lifestyle - has become an important driver for HCC development. Immunotherapy has been recently approved for HCC but stratification of responders versus non-responders has remained an unmet need 5–8. Here, we found a progressive accumulation of non-classical activated CD8+PD-1+ T-cells in livers of NASH-affected patients and mice. PD-L1/PD-1-targeted immunotherapy of NASH-induced HCC administered either at cancer-initiation or after cancer-establishment lacked beneficial effects in mice. On the contrary, PD-1-targeted immunotherapy drove hepatic necro-inflammation and increased liver cancer incidence, tumor number, and nodule size. Anti-CD8 or anti-CD8/anti-NK1.1 treatment suppressed liver cancer development, implicating CD8+ T-cells as liver cancer drivers in the context of NASH. In line, PD-1-/- mice challenged with a NASH-inducing diet displayed early-onset of liver cancer. Mechanistically, PD-1-targeted immunotherapy triggered necro-inflammation and a pro-tumorigenic environment in the context of NASH, increasing the abundance of hepatic TOX+CXCR6+ expressing CD8+PD-1+ TNF+ T-cells. Anti-CD8/anti-PD-1 or anti-TNF/anti-PD-1, but not anti-CD4/anti-PD-1 treatment reverted anti-PD1 treatment-related increase of liver inflammation, NASH severity and tumorigenesis. Gene expression profile and increased abundance of murine hepatic CD8+PD-1+ T-cells were corroborated in human CD8+PD-1+ T cells derived from NASH patients. In a meta-analysis of clinical trials testing PD-1-targeting immune checkpoint inhibitors alone (i.e. pembrolizumab) or in combination in 1656 patients with advanced HCC, immunotherapy was not favorable over to control treatment in non-viral- when compared to viral-related HCC. Similarly, in two clinical cohorts tested, patients with NASH-driven HCC had a significantly worse overall survival with PD-1-targeted immunotherapy than HCC patients with other etiologies. Our data identify non-viral etiologies, particularly NASH, as potentially non-responsive in the context of HCC immunotherapy, providing a strong rational basis for patient stratification.

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Therapeutic modulation of NKG7 in CD8+ T cells increases anti-tumor cytotoxicity and improves response to immune checkpoint inhibitors

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