Unmasking Immunomodulatory Effects of Radiation in Synovial and Myxoid/ Round Cell Liposarcoma
Outcomes remain poor for patients with metastatic Synovial Sarcoma (SS) and Myxoid/ round cell liposarcoma (MRCL). Immunotherapies including T cell based therapies and checkpoint inhibitors have eradicated tumors and improved the survival of patients with certain cancer types. There is an urgent need to extend these approaches to sarcoma. Immunotherapeutic approaches may be well suited to SS and MRCL because both of these sarcoma subtypes characteristically express high levels of NY-ESO-1 and other cancer testis antigens, immunogenic proteins typically seen in the germ cells of testis, some cancers but not other normal tissues in adults. Interestingly, while brisk T cell infiltrates are frequently seen in other NY-ESO-1 expressing cancers like ovarian cancer and melanoma, these are unusual in SS and MRCL tumors. Similarly, NY-ESO-1 specific T cell populations are often easily identifiable in the blood of ovarian cancer and melanoma patients where as we have not observed them in the blood of SS and MRCL patients. By pulsing dendritic cells with NY-ESO-1 peptide in vitro we are able to consistently stimulate, sort and expand highly active NY-ESO-1 specific T cells from the blood of SS and MRCL patients, so we know they are capable of producing an NY-ESO-1 specific response.
We have identified two potential mechanisms of immune evasion in SS and MRCL tumors: Low MHC expression and infiltration of high levels of CD68+ cells (potentially myeloid derived suppressor cells and/or tumor associated macrophages). Radiation, particularly when given to tumors at high doses and in few fractions, has the potential to increase MHC expression and eliminate myeloid/macrophage cells. Radiation has been successfully incorporated into several trials of systemic immunomodulatory agents with beneficial effect. In this proposal, we will dissect the immunologic changes that occur following local radiation both in the tumor microenvironment and systemic circulation for the purpose of developing novel immunotherapeutic strategies to treat these sarcoma types.
The specific aims of this proposal are:
Aim 1: To examine whether radiation increases tumor cell MHC expression, reduces CD68+ myeloid infiltration, and elicits an antigen specific T cell response in SS and MRCL.
In this Aim, biopsies will be collected from patients undergoing high dose, hypo-fractionated radiation before and after radiation. Our hypothesis is that radiation will increase MHC expression, decrease the number of CD68+ cells and increase T cell infiltration in the tumor.
Aim 2: To test whether radiation induces a systemic tumor-specific inflammatory response in SS and MRCL.
In this Aim patients will have peripheral blood collected before and at multiple time points following radiation. Our hypothesis is that radiation will induce a systemic tumor specific immune response.