Abstract 616: Interferon gamma induced transformation of the cold tumor microenvironment in patients with NY-ESO-1 expressing sarcomas
Authors: Zhang Shihong , Cooper Sara , Donahue Bailey , Pillarisetty Venu G. , Jones Robin L. , Riddell Stanley R. , Tine Brian A. Van , Pollack Seth M. 
Published: August 2018

Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) cells homogeneously express high levels of NY-ESO-1 and other cancer/testis antigens, which makes these sarcoma types good candidates for T cell immunotherapy. However, these tumors demonstrate a “cold” microenvironment, with low cell surface expression of human leukocyte antigen (HLA) molecules and few infiltrating T cells. Interferon gamma (IFNγ) has been used both as a single agent and in combination with other immunotherapies in cancers with “hot”, highly inflamed tumor microenvironments such as melanoma. To date, little work has explored its impact on immunologically quiet tumors. In order to increase the expression of HLA on the tumor cell surface and improve the T cell recognition and cytotoxicity, we initiated a pilot “window of opportunity” clinical trial, 6 SS/MRCL patients were treated with subcutaneous systemic interferon gamma (IFNγ) weekly for 2 or 4 weeks at a dose of 100 mcg/m2. The primary objective of the study was to determine if HLA expression increased on post-treatment biopsies in comparison to pre-treatment biopsies. The treatment was relatively well-tolerated, patients experienced flu-like symptoms with no severe adverse effects. Patients' sera, PBMCs and tumor biopsies were collected pre- and post-IFNγ treatment for further analysis. Several cytokines including interleukin-16, microphage migration inhibitory factor and CXCL-10 etc. changed considerably in patients' periphery. Transcriptome profiling on the PBMCs showed significant changes in some immune regulatory genes in T cells and monocytes. Flow cytometry analysis of the tumor biopsies showed significant increase of both class I and class II HLA on the tumor surface in all treated patients. Tumor infiltrating immune cell frequencies increased by 3-10 times, of which, the majority were T cells. Functional assay of expanded tumor infiltrating lymphocytes (TIL) showed an increased and broadened tumor-associated peptide recognition capability. However, in all evaluable tumors there was an increase in PD-L1 either on tumor or on infiltrating macrophages. In conclusion, weekly IFNγ treatment is well tolerated in SS/MRCL patients and it can significantly enhance the expression of HLA on tumor surface, and increase T cell infiltration; however, increased PD-L1 expression on tumor cells and infiltrating immune cells may help tumors evade T cell elimination. Strategies combining PD-1 blockade and IFNγ should be explored.

Citation Format: Shihong Zhang, Sara Cooper, Bailey Donahue, Venu G. Pillarisetty, Robin L. Jones, Stanley R. Riddell, Brian A. Van Tine, Seth M. Pollack. Interferon gamma induced transformation of the cold tumor microenvironment in patients with NY-ESO-1 expressing sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 616.