The role of CCR8 chemokine system in Treg-mediated tumor resistance to immune checkpoint blockade

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Regulatory T cells (Tregs) are a subset of CD4+ T cells that are responsible to maintain the periphery tolerance and keep the immune response “in check”. However, just like two sides of a coin, the presence of Tregs in the tumor microenvironment can dampen the anti-tumor immunity and promote tumor progression, which is a major obstacle to successful immunotherapy. Chemokines and their receptors orchestrate the immune cell trafficking and intracellular interactions, thus are key regulators of immune responses. However, the chemokine systems that mediate the tumor infiltration of Tregs are poorly defined. Recent studies demonstrated that CCR8 expressing Treg cells are enriched in many human cancers, including breast carcinoma, melanoma, and lung adenocarcinoma. CCR8 is the receptor for the chemokines CCL1 (mouse and human), CCL8 (mouse), and CCL18 (human). The CCR8+ Tregs exhibit a highly activated and immunosuppressive phenotype, and their depletion elicits anti-tumor responses that are synergistic with anti-PD-1 immunotherapy. However, how the CCR8 chemokine system regulates Treg functions and therefore the tumor resistance to immune checkpoint blockade therapy remains unclear. Using a murine melanoma model and various newly generated reagents, including CCR8 deficient mice, CCR8 reporter mice, CCR8 ligands reporter mice, and neutralizing antibodies, we aim to solve this question. We envision that generated findings will provide novel strategies to overcome the tumor resistance to immunotherapy and benefit more cancer patients.

The image shows the presence of Treg cells (marked by blue and green) in mouse melanoma and their interaction with CD8+ T cells (marked by magenta).