The expression and function of PD-1 expressing regulatory T cells of cancer patients

Abstract

Regulatory T (Treg) cells have been well known to suppress effector T

cells, and thus render them functionally insufficient to attack cancer cells. Although inhibitory molecules such as programmed death-1 (PD-1) expressed by conventional T (Tconv) cells play a key role in causing immune tolerance in cancer patients, the function of PD-1 expressed by Treg cells are not clearly studied. We aim to evaluate the expression and function of PD-1 on Tconv and Treg cells in various tumor microenvironments and suggest the impact on anti-PD-1 treatment for cancer patients. We collected 72 malignant effusion/peripheral blood specimens from stage IV cancer patients and 31 tumor tissue/ peripheral blood samples from patients who underwent surgery. Lymphocytes from malignant effusions, tumor tissues, and peripheral bloods were analyzed for subtype of Tconv and Treg cells, and their PD-1, CTLA-4, and TIM-3 expressions using by flow cytometry. Using lung tumor mouse model, we investigated the function of PD-1 expressing tumor infiltrating Treg cells. The PD-1 on CD4+ and CD8+ Tconv cells was highly expressed in tumor tissues and malignant effusion compared to peripheral blood. Interestingly, upregulation of PD-1 on Treg cells in tumor tissues and malignant effusions compared to peripheral blood was even more distinguishable than that on CD4+ and CD8+ Tconv cells. Whereas, the changes of other immune inhibitory molecules such as CTLA-4 or TIM-3 on Treg cells among three different samples were negligible. There was no significant difference in frequencies of PD-1 expressing CD4+, CD8+ Tconv cells, and Treg cells in malignant effusions in six different types of cancers. The upregulation of PD-1 on Treg cells in malignant effusions and tumor tissues could reflect immune exhaustion in cancer patients. PD-1 expressing Treg cells might reinforce the immune suppressive function in tumor microenvironment. The malignant effusion derived from stage IV cancer patients can reflect tumor microenvironment similar with tumor tissue. The upregulation of PD-1 on Treg cells in malignant effusions and tumor tissues could reflect immune exhaustion in cancer patients