Influence of Tregs on the phenotype of monocytes/macrophages in the tumor microenvironment and on response of Oral Squamous Cell Carcinoma to cytotoxic chemotherapy

Abstract

Oral Squamous Cell Carcinoma (OSCC) is frequently diagnosed in advanced stages, in which prognosis is dim. Even when long-term survival is achieved, usually there is high morbidity associated with psychological/esthetic and functional impairment. Morbidity is related with surgical resection as the primary therapeutic approach, which may or may not be associated with cytotoxic (chemo/radio) therapy. In the last few decades, inhibitors of EGF receptor and of suppressor immunecheckpoints were added to the therapeutic toolbox of OSCC, but the clinical benefits are limited in magnitude and, especially, in the percentage of responding patients. This highlights the importance of improving the understanding of the pathogenesis and, particularly for immunomodulatory approaches, the mechanisms involved in immune regulation in OSCC. Therapeutic approaches aiming at the rescue of anti-tumoral immunity can synergize with strategies that attenuate the immunosuppressive state. OSCC is an immunosuppressive tumor and prognosis is worse in cases with higher infiltration by suppressive immune cells, such as M2-like macrophages and regulatory T cells (Tregs). Evidence demonstrates a positive feedback loop in the crosstalk between M2 macrophages and Tregs, but information in the context of OSCC is scarce. The main hypothesis in this proposal is that trasient inhibition/depletion of Tregs alleviates immunosuppression, favoring anti-tumoral immunity by skewing macrophages to the M1 phenotype and increasing infiltration by CD8+ T cells. The resulting change of the tumor microenvironment (TME) may set the stage for increased effectiveness of both traditional and immunomodulating therapies, as well as reduce the recurrence. We propose in vitro (3D spheroid cultures) to assess the reciprocal crosstalk between macrophages and Tregs in the TME. In vivo, we will use a syngeneic OSCC model in transgenic immunocompetent mice assessing the influence of transient depletion of Tregs, in different 'windows of opportunity', on tumor progression, efferocytosis and response to cytotoxic treatment. (AU)