Adaptive immune contexture at the tumour site and downmodulation of circulating myeloid-derived suppressor cells in the response of solitary fibrous tumour patients to anti-angiogenic therapy

• Published in: British journal of cancer 2014-09, Vol.111 (7), p.1350-1362
• Main Authors: Tazzari, M, Negri, T, Rini, F, Vergani, B, Huber, V, Villa, A, Dagrada, P, Colombo, C, Fiore, M, Gronchi, A, Stacchiotti, S, Casali, P G, Pilotti, S, Rivoltini, L, Castelli, C
• Format: Article
• Language: English
• Subjects: 692/699/67/1059/2325; 692/699/67/1798; 692/699/67/580; Adaptive immunity; Adaptive Immunity - drug effects; Adult; Aged; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Dermatology; Disease-Free Survival; Drug Resistance; Epidemiology; Female; Humans; Immune system; Immunology; Immunosuppression; Indoles - pharmacology; Indoles - therapeutic use; Laboratories; Lymphocytes; Lymphocytes - drug effects; Lymphocytes - immunology; Male; Medical sciences; Microscopy; Middle Aged; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Myeloid Progenitor Cells - drug effects; Myeloid Progenitor Cells - immunology; Oncology; Pathology; Pyrroles - pharmacology; Pyrroles - therapeutic use; Sarcoma; Solitary Fibrous Tumors - blood; Solitary Fibrous Tumors - drug therapy; Solitary Fibrous Tumors - immunology; Translational Therapeutics; Treatment Outcome; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tumors; Tumors of the skin and soft tissue. Premalignant lesions
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2014.437

Background: Host immunity is emerging as a key player in the prognosis and response to treatment of cancer patients. However, the impact of the immune system and its modulation by therapies are unknown in rare soft tissue sarcomas such as solitary fibrous tumours (SFTs), whose management in the advanced forms includes anti-angiogenic therapy. Here, we studied the in situ and systemic immune status of advanced SFT patients and the effects of sunitinib malate (SM) in association with the clinical efficacy. Methods: Immune contexture of SFTs was assessed by immunohistochemistry in lesions from untreated or SM-treated patients. Frequency of circulating myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and T-cell functions was assessed ex vivo in SFT patients prior and during anti-angiogenic therapy. Patients with long-term tumour control were included to correlate immune profiles and clinical responses. Results: Anti-angiogenic naïve SFT lesions were heavily infiltrated by CD163 + CD14 + CD68 − and CD163 + CD14 − CD68 − myeloid cells but devoid of T cells. Conversely, post-SM tumours acquired a new subset of CD68 + CD14 + myeloid cells and displayed traits of an on-going adaptive immunity, strongly enriched in activated CD8 + and CD4 + T cells. These changes at the tumour site paralleled the alleviation of systemic immunosuppression and the drop in the frequency of circulating monocytic MDSCs (mMDSCs) and granulocytic MDSCs (gMDSCs). Rebound in the number of mMDSCs, but not of gMDSCs occurred at disease progression, and a reduced percentages of mMDSCs, comparable to those found in healthy donors (HDs), endured only in the SM-responsive patients. Conclusions: The immune contexture of SFT patients is heavily involved in anti-angiogenic therapy and it could be exploited to achieve more durable disease control through immune-based combination strategies.