Role of tumor-infiltrating regulatory T cells according to the presence of tertiary lymphoid structures in human lung cancer

Regulatory T cells (Tregs) exert various suppressive mechanisms to dampen the host immune response which can help tumor cells to escape immune surveillance. However, the prognostic value of tumor-infiltrating Tregs (Ti-Tregs) is controversial based on the expression of FoxP3 marker in cancer patients. Here, we decipher the phenotype of Tregs infiltrating human lung cancer to determine their role in shaping the immune response against tumor cells. Our aim was to study the differentiation, activation, and immunosuppression status of Ti-Tregs in different areas of human lung tumors. Immunohistochemistry was performed on paraffin-embedded tissue sections for CD3 and FoxP3 stainings, and phenotypic analysis was carried out on fresh human lung cancer specimens (n=50) by flow cytometry. In lung cancer patients, Ti-Tregs localize in the different part of the tumor i.e. tumor nests, stroma, and tertiary lymphoid structures (TLS). Ti-Tregs are CD4+ and show central-memory and effector-memory phenotype. Interestingly, Ti-Tregs exhibit different phenotypes based on the differential expression of activation and immunosuppression molecules. In conclusion, the presence of several Ti-Treg subsets in lung tumor suggests that they may play different roles in distinct tumor areas. Thus, the next step will be to decipher the mechanisms and functions used by these Treg populations in order to manipulate them for therapeutic intervention.