Radiotherapy of Human Sarcoma Promotes an Intratumoral Immune Effector Signature

Abstract

Purpose: The tumor immune microenvironment plays a crucial role in the development and progression of cancer. Sarcomas are a group of heterogeneous soft tissue malignancies that are often treated with radiotherapy as a part of the treatment concept. There is increasing evidence that radiotherapy leads to alterations in the tumor microenvironment, particularly with respect to the immune infiltrate. This study has been carried out to develop a better understanding of such changes following radiotherapy.Experimental Design: We retrospectively analyzed the expression of 35 immune response-related genes by quantitative reverse transcription PCR analysis and immunohistochemistry on paired formalin-fixed paraffin-embedded tumor samples from 38 sarcoma patients before and after radiotherapy.Results: We observed that radiotherapy results in a significant upregulation of several immune effectors and cancer-testis antigens and a concomitant downregulation of immune suppressors, indicating that radiotherapy may support the immune defense in sarcomas.Conclusions: These novel findings may have implications for the design of therapeutic regimens which exploite the immune system in sarcoma patients by combining standard radiotherapy with immunotherapeutic strategies.

HSP90 inhibition as a means of radiosensitizing resistant, aggressive soft tissue sarcomas

“…This is of importance for the induction of systemic anti-tumor immune mechanisms, which can target locally surviving tumor cells as well as distant metastases. Since sarcoma radiotherapy has been reported to be associated with accumulating markers of immune effectors paralleled by downregulation of immune suppressors in tumor samples, this might add another facet of anti-tumor efficacy in the context of radiotherapy combined with HSP90 inhibition [49]. It will be of special interest to delineate the importance of the mode of cell death in this scenario with particular focus on the involvement of irradiationinduced senescence.…”

Safety of selective internal radiation therapy (SIRT) with yttrium-90 microspheres combined with systemic anticancer agents: expert consensus

“…Promotion and suppression of tumorspecific immunity have been described in association with radiotherapy, and depend on whether the elicited inflammation is acute or chronic. Acute inflammation is a potent stimulator of anti-tumor immunity through a variety of mechanisms, including activation of tumor-associated dendritic cells (71), expression of cancer-testis (CT) and MHC class I antigens on the tumor surface (72), and tumor infiltration by CD8+ T cells (73). Promotion of anti-tumor immunity in the context of acute inflammation is critically dependent upon transient complement activation involving local production of C3a and C5a anaphylatoxins (74).…”

Combining Immunotherapy and Radiation for Prostate Cancer

“…1,35,[43][44][45][46] The preclinical evidence for synergy between radiotherapy and immunotherapy has been reviewed recently by Kwilas et al 45 and we therefore focus herein on recent clinical data.…”