Abstract 4062: Role of CD137 signaling in immune evasion of Hodgkin and Reed-Sternberg cells

Abstract

Abstract Hodgkin lymphoma (HL), a lymphoid malignancy, is a frequently occurring cancer among adolescents and young adults. HL is marked by the presence of malignant Hodgkin and Reed-Sternberg (HRS) cells, which constitute only a small fraction of the tumor mass. HRS cells are present in a complex stroma of inflammatory leukocytes, but are often able to evade the host immune system. These cells express various receptors to recruit leukocytes and hijack them for supporting the tumor growth. Our group has reported the overexpression of CD137, a member of the tumor necrosis factor receptor (TNFR) superfamily, on the HRS cells of HL tumor samples. CD137 is a co-stimulatory molecule expressed by T cells, only upon activation. We speculated that the expression of CD137 on the HRS cells may be associated with its malignancy, as HRS cells are clonally derived from B cells which are not expressing CD137. Our study aims to analyse the functional role of CD137 expression behind the survival, progression, and cytokine release of the malignant HRS cells. We found that the induction of CD137 signaling in HRS cell lines enhanced the secretion of cytokines such as IL-6, TNF-α and IL-13. In order to investigate the effect of these cytokines on the immune microenvironment, we cultured peripheral blood mononuclear cells (PBMCs) in the supernatants derived from CD137-induced HRS cells. PBMCs, when cultured in the above mentioned conditioned supernatants, secreted lesser levels of IFN-γ (a Th1 cytokine essential for T cell and NK cell cytotoxicity), implying a suppressed state of immune cells. Further, neutralisation of IL-13 (a Th2 cytokine) in the conditioned supernatants reversed the reduction of IFN-γ observed in PBMCs. This shows that IL-13 secreted by the HRS cells upon CD137 signaling is responsible for the inhibition of IFN-γ secretion by PBMCs. To summarize, CD137 signaling in HRS cells leads to the secretion of cytokines, which drive the polarization of helper T cells towards Th2 type, thus reducing Th1 immune responses against cancers. Taken together, our findings reveal the role of CD137 signaling as a novel mechanism of immune escape in HRS cells. Hence, targeting CD137 can be a potential therapeutic option for HL patients. Citation Format: Sakthi Rajendran, Herbert Schwarz. Role of CD137 signaling in immune evasion of Hodgkin and Reed-Sternberg cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4062. doi:10.1158/1538-7445.AM2015-4062