Abstract 3644: Targeting the CD51/TGF-beta pathway: a potential innovative cancer immunotherapy in T-cell lymphomas

Abstract T-cell lymphomas are a heterogeneous group of malignancies involving T lymphocytes and generally characterized by a poor prognosis. Among them, cutaneous T-cell lymphomas (CTCL) involve primarily the skin. The most frequent CTCL are mycosis fungoides and Sézary syndrome (SS) (1). There is no cure for advanced-stage CTCL, the remissions are generally rare and short, and the overall survival is around 5 years with an impaired quality of life. Thus, the development of new treatments inducing longstanding responses in CTCL is a major unmet need (2). Because Sézary cells express several Treg markers as PD-1, ICOS, CD39 or CCR8 (3), we analyzed the expression of CD51, the αV integrin, which is expressed with the β8 integrin on Treg cells (4). CD51 is involved in the production of active form of TGF-β, a cytokine with immunosuppressive properties that promotes tumor escape. Thus, targeting the αVβ8 integrin with a specific antibody has been shown to inhibit TGF-β activation while not inhibiting cell adhesion (5). Our results revealed that CD51 is significantly overexpressed in circulating lymphocytes from SS patients as compared to healthy individuals. Interestingly, CD51 is not associated with the β8 integrin but with CD29 (β1 integrin), and CD61 (β3 integrin) in some patients.CD51/CD29 and/or CD51/CD61 heterodimers appear as potential therapeutic targets in T-cell lymphoma, which may be associated with the production of active TGF-β. Targeting these heterodimers with specific antibodies to prevent the release of active TGF-β could improve patient’s antitumor immune response. They could also represent depleting targets through NK or CAR-T cells activities as shown in diffuse intrinsic pontine glioma and glioblastoma for CD51/CD61 heterodimer (6). 1. Dobos G, et al. Epidemiology of Cutaneous T-Cell Lymphomas: A Systematic Review and Meta-Analysis of 16,953 Patients. Cancers. 11 oct 2020;12(10).2. Scarisbrick JJ, et al. The changing therapeutic landscape, burden of disease, and unmet needs in patients with cutaneous T-cell lymphoma. Br J Haematol. févr 2021;192(4).3. Giustiniani J, et al. CCR8 is a new therapeutic target in cutaneous T-cell lymphomas. Blood Adv. 2022 Feb 24.4. Stockis J, et al. Blocking immunosuppression by human Tregs in vivo with antibodies targeting integrin αVβ8. Proc Natl Acad Sci U S A 2017 Nov 21;114(47).5. Tsui P, et al. The TGF-β inhibitory activity of antibody 37E1B5 depends on its H-CDR2 glycan. mAbs. janv 2017;9(1):104-13.6. Cobb D, de Rossi J, Liu L, An E, Lee D. Targeting of the alphav beta3 integrin complex by CAR-T cells leads to rapid regression of diffuse intrinsic pontine glioma and glioblastoma J Immunother Cancer 2022. Citation Format: Jérôme Giustiniani, Anne Marie-Cardine, Sadjia Belkhelouat, Martine Bagot, Armand Bensussan, Nicolas Ortonne, Adèle De Masson. Targeting the CD51/TGF-beta pathway: a potential innovative cancer immunotherapy in T-cell lymphomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3644.