OX40 regulatory T cells in cutaneous squamous cell carcinoma suppress effector T cell responses and associate with metastatic potential

Abstract

Purpose: Cutaneous squamous cell carcinoma (cSCC) is the most common human cancer with metastatic potential. Despite T cells accumulating around cSCCs, these tumors continue to grow and persist. To investigate reasons for failure of T cells to mount a protective response in cSCC, we focused on regulatory T cells (Tregs) as this suppressive population is well represented among the infiltrating lymphocytes.
Experimental Design: Flow cytometry was conducted on cSCC lymphocytes and in vitro functional assays were performed using sorted tumoral T cells. Lymphocyte subsets in primary cSCCs were quantified immunohistochemically. Results: FOXP3+ Tregs were more frequent in cSCCs than in peripheral blood (p<0.0001, n=86 tumors). Tumoral T_regs suppressed proliferation of tumoral effector CD4⁺ (p=0.005, n=10 tumors) and CD8⁺ T cells (p=0.043, n=9 tumors) and inhibited interferon-γ secretion by tumoral effector T cells (p=0.0186, n=11 tumors). The costimulatory molecule OX40 was expressed predominantly on tumoral Tregs (p<0.0001, n=15 tumors) and triggering OX40 with an agonist anti-OX40 antibody overcame the suppression exerted by T_regs, leading to increased tumoral effector CD4⁺ lymphocyte proliferation (p=0.0098, n=10 tumors). T_regs and OX40⁺ lymphocytes were more abundant in primary cSCCs which metastasized than in primary cSCCs which had not metastasized (n=48 and n=49 tumors respectively).
Conclusions: T_regs in cSCCs suppress effector T cell responses and are associated with subsequent metastasis, suggesting a key role for T_regs in cSCC development and progression. OX40 agonism reversed the suppressive effects of T_regs in vitro, suggesting that targeting OX40 could benefit the subset of cSCC patients at high risk of metastasis.

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Identifiers

ORCID for Aymen Al-Shamkhani: orcid.org/0000-0003-0727-4189

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