Abstract 5153: The role of CCL22-specific CD4 T cells in modulating the immunosuppressive tumor microenvironment in ovarian cancer

Abstract

Abstract Background: CCL22, a macrophage-derived chemokine, is overexpressed in ovarian cancer and exerts immunosuppressive functions by the recruitment of regulatory T cells (Tregs) to the tumor microenvironment (TME). Our research group described naturally occurring T cells specific for an MHC class I epitope derived from CCL22. CD8+ CCL22-specific T cells isolated from cancer patients could recognize CCL22-expressing cells and decrease the levels of CCL22 in ovarian ascites in vitro. Expansion of CCL22-specific CD8+ T cells in animal models of cancer by peptide vaccination led to a therapeutic anti-tumor effect by reducing Treg recruitment into the TME. In this study we aimed at characterizing CD4+ CCL22-specific T cells and their potential for modulating the tumor microenvironment in ovarian cancer. Methods: CCL22-responses were screened with a library of overlapping 20mer peptides covering the entire sequence of CCL22 in PBMCs from healthy donors and ovarian cancer patients. CCL22-specific T cells were isolated from PBMCs and ovarian ascites for functional characterization through IFNγ ELISpot and ICS against peptides and CCL22-expressing target cells. Cytokine secretion was measured with protein multiplex immunoassays. Vaccination and therapeutic efficacy were evaluated in BALB/c CT26 and 4T1 syngeneic models. Results: We identified an immunogenic region in the CCL22 protein sequence and detected CD4 T-cell responses against CCL22-derived peptides in healthy donors and ovarian cancer patients through IFNγ ELISpot. CCL22-specific CD4+ cells have also been identified ex vivo in the ascites fluid from patients with ovarian cancer. We isolated and expanded CCL22-specific CD4+ T-cell clones from the ovarian ascites and demonstrated their reactivity against CCL22-producing cell lines. Furthermore, the stimulation of CCL22-specific CD4+ T cells in the PBMC culture and ascites samples was associated with a modulation of the cytokine environments. Additionally, vaccination with surrogate murine 20mer and MHC-II restricted CCL22-derived peptides lead to successful induction of specific T-cell responses in the spleens and draining lymph nodes of vaccinated animals. Activation of such CCL22-specific CD4 T cell responses was associated with a therapeutic effect seen as reduction of the tumor growth in different models of cancer. Conclusion: This study provides evidence for the ability of pro-inflammatory CD4+ CCL22-specific T cells to modulate the tumor microenvironment, particularly in ovarian cancer. Altogether we provide the rationale for the development of a CCL22-based immune modulatory vaccination for ovarian cancer. Citation Format: Ines Lecoq, Evelina Martinenaite, Marie C. Westergaard, Inge Marie Svane, Mads H. Andersen. The role of CCL22-specific CD4 T cells in modulating the immunosuppressive tumor microenvironment in ovarian cancer. [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 5153.