Squamous Cell Tumors Recruit γδ T Cells Producing either IL17 or IFNγ Depending on the Tumor Stage

Abstract

The identification of reciprocal interactions between tumor-infiltrating immune cells and the microenviroment may help us understand mechanisms of tumor growth inhibition or progression. We have assessed the frequencies of tumor-infiltrating and circulating γδ T cells and regulatory T cells (Treg) from 47 patients with squamous cell carcinoma (SCC), to determine if they correlated with progression or survival. Vδ1 T cells infiltrated SSC tissue to a greater extent than normal skin, but SCC patients and healthy subjects had similar amounts circulating. However, Vδ2 T cells were present at higher frequencies in circulation than in the tissue of either cancer patients or healthy donors. Tregs were decreased in the peripheral blood of SCC patients, but were significantly increased in the tumor compartment of these patients. Tumor-infiltrating γδ T cells preferentially showed an effector memory phenotype and made either IL17 or IFNγ depending on the tumor stage, whereas circulating γδ T cells of SCC patients preferentially made IFNγ. Different cell types in the tumor microenvironment produced chemokines that could recruit circulating γδ T cells to the tumor site and other cytokines that could reprogram γδ T cells to produce IL17. These findings suggest the possibility that γδ T cells in SCC are recruited from the periphery and their features are then affected by the tumor microenvironment. Elevated frequencies of infiltrating Vδ2 T cells and Tregs differently correlated with early and advanced tumor stages, respectively. Our results provide insights into the functions of tumor-infiltrating γδ T cells and define potential tools for tumor immunotherapy. .

γδ cells and tumor microenvironment: A helpful or a dangerous liason?

“…Recently, we have assessed the frequencies of tumor‐infiltrating and circulating γδ T cells in patients with squamous cell carcinoma (SCC) showing that Vδ1 T cells infiltrate SSC tissue at higher levels than found in normal skin and in PBMC of SCC patients and healthy subjects, whereas Vδ2 T cells showed higher frequency in PBMC than in the tissue either in cancer patients than in healthy donors. We have also observed a correlation between cytokine‐producing intratumoral Vδ1 and Vδ2 T cells and clinicopathological‐staging and follow‐up data of SCC …”

“…We have also observed a correlation between cytokine-producing intratumoral V 1 and V 2 T cells and clinicopathological-staging and follow-up data of SCC. 28 In another study, we also have found that T cells are a minor population among colon cancer-infiltrating leukocytes and their abundance correlate with better clinical outcome, indicating that they are probably involved in controlling tumor growth at an early stage of disease. 29 However, a recent analysis of expression signatures from ∼18,000…”

“…In fact, it is well known that γδ T cells may be induced to IL‐17 production by combinations of IL‐6, TGF‐β, IL‐1β, and IL‐23 . As supposed, IL‐6, IL‐1β, IL‐23, and TGF‐β were produced and released in conditioned medium by CSC, sphere‐derived adherent cells (SDAC), and CAF, thus making the environment conducive for differentiation of γδ17 T cells …”

“…In our study in SCC, tumor‐infiltrating γδ Τ cells made both IL‐17 and IFN‐γ, thus differing from circulating γδ of SCC patients, which preferentially made IFN‐γ. Moreover, the levels of IL‐17‐producing γδ T cells among tumor‐infiltrating lymphocytes were significantly higher in SCC patients with advanced disease, whereas the levels of IFN‐γ‐producing γδ T cells were higher in SCC patients at early stage of disease, clearly indicating that the immune response is skewed toward IL‐17‐producing cells …”

Role of Type I and II Interferons in Colorectal Cancer and Melanoma

“…Beyond all the above-mentioned direct effects, IFNs can also indirectly regulate tumor cell growth, affecting different biological processes involved in tumor progression, such as angiogenesis and immunity (26, 27). The first demonstration of an indirect effect has been highlighted by Brouty-Boye and colleagues who showed that the administration of IFNs increased the survival of mice affected by lymphocytic leukemia, regardless of the intrinsic sensibility of tumor cells to IFN preparations (28).…”