IMMUNOLOGICAL SIGNATURE IN NAÏVE AND SUNITINIB-TREATED SOFT TISSUE SARCOMA PATIENTS: ROLE OF MYELOID CELLS

Although designed to directly target cancer cells and tumor associated-vasculature, anti-angiogenic drugs (e.g. sunitinib), have been described to influence tumor-host interactions. Sunitinib is currently in use at our Institute for the treatment of progressive, advanced soft tissue sarcomas (STS) of different histology. However, the systemic and local immune responses and their modulation by anti-angiogenic therapies are unknown in these neoplasms, namely solitary fibrous tumors (SFTs), clear cell sarcoma (CCS) and alveolar soft part sarcoma (ASPS). This thesis aims to shed light on the immunological status of these STS patients and to address the question to which extent sunitinib induces immune modulation in these patients. Thus, my research focused on the characterization of both tumor-infiltrating and circulating immune cells of STS patients. Fine analysis of the immune contexture at the tumor site in naïve and in sunitinib-treated tumors revealed that myeloid cells, namely tumor-associated macrophages, represent a key component of the tumor microenvironment and that their reprogramming is part of the response to sunitinib treatment. Immune monitoring of circulating cells in these STS patients indicated that circulating myeloid suppressor cells were associated to disease progression and were the major player in mediating the immune-suppressive status in naïve and in sunitinib-treated SFT patients. Moreover, evidence have been provided that, in sunitinib-treated SFT patients, myeloid suppressor cells may be part of acquired resistance, thus supporting the notion that myeloid cells are the most relevant hurdle in the efficacy of anti-angiogenic treatments. Collectively the results of this thesis shed light on an unappreciated phenomenon of immune dysfunction in STS patients and indicate that in SFTs sunitinib transiently relieves systemic immunosuppression and reprograms the immune microenvironment. Moreover, for the first time, an antigen-specific T cell response has been evidenced in CCS, and, this tumor-specific response has occurred in association to sunitinib-induced immune modulation. Overall, this thesis poses the rationale for the development of immune-based clinical approaches aimed at achieving a more durable disease control in these cancer patients, for which effective medical therapies are still needed.