Immunosuppression mediated by regulatory CD8+ T cells in lung cancers

Lung cancer is a common and deadly malignancy, accounting for the highest number of cancer-related deaths worldwide. It is divided into two main types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Despite groundbreaking advancements in cancer treatment using immune checkpoint blockades (e.g., anti-PD-1/CTLA-4 antibodies), the clinical benefits for lung cancer patients are modest, with a significant fraction of patients failing to respond. Thus, there is an urgent need to improve our understanding of immune evasion mechanisms and develop new therapies to enhance immunotherapy for lung cancer patients. We recently identified KIR+CD8+ T cells as a new type of immunosuppressive cells in humans, which are functional and phenotypic equivalent of Ly49+CD8+ T cells in mice. These cells are elevated in the blood and inflamed tissues of patients with autoimmune or infectious diseases, where they contribute to peripheral tolerance by eliminating pathogenic T cells via their cytolytic activity. Since many tumor antigens are derived from self-molecules, we asked whether these cells are also induced in the tumor microenvironment (TME) to suppress anti-tumor immunity. Our preliminary data showed an increased activity in Ly49+CD8+ T cells in KrasG12DLkb1-/- (KL) NSCLC-bearing mice treated with anti-PD-1 plus anti-CTLA-4 therapy, and depleting these cells significantly enhanced anti-tumor T cell responses in this model. Therefore, we hypothesize that regulatory CD8+ T cells contribute to immune suppression and therapy resistance in lung cancers, and targeting these cells could improve immunotherapy efficacy. To test this hypothesis, we will leverage our innovative murine orthotopic lung cancer models and patient specimens to profile regulatory CD8+ T cells across different lung cancer subtypes and in response to immunotherapy. We will elucidate the mechanisms by which regulatory CD8+ T cells mediate immunosuppression in the TME and assess their potential as therapeutic targets to enhance sensitivity to immunotherapy. Our study may unravel a novel role of regulatory CD8+ T cells in regulating anti-tumor immunity and modulating responses to immunotherapy. By uncovering new cellular dynamics and immunosuppressive mechanisms within the TME, our findings could fundamentally reshape our current understanding on immunosuppression in cancer and support regulatory CD8+ T cells as a new therapeutic target to improve sensitivity to immunotherapy in cancer treatment. Project Number: 1R21CA301104-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: JING LI (+1 co-PI) | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $408,829 | Activity Code: R21 | Study Section: Therapeutic Immune Regulation Study Section[TIR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11303011