ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1670841
This article is part of the Research TopicCombination Immune Therapies for the Treatment or Prevention of Breast or Gynecological CancersView all articles
Enhanced Anti-Tumor Efficacy of Tumor-Infiltrating Lymphocytes by GITR agonist in Ovarian Cancer
Provisionally accepted
- CHA Bundang Medical Center, sungnam, Republic of Korea
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Background: Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TILs) is a personalized immunotherapy that has shown promising clinical results in various tumor types. Although TILs are associated with improved survival in patients with ovarian cancer (OC), their therapeutic efficacy remains limited. Therefore, novel strategies to enhance the anti-tumor activity of TILs are needed to improve outcomes in OC treatment. Methods: Single cells were isolated from tumor tissues of patients with high-grade serous carcinoma (HGSC) and expanded for 14 days in the presence of IL-2 under four different conditions: (1) control (W), (2) PD-1 antagonist (WI), (3) PD-1 antagonist + IL-15 + IL-21 (WIO), and (4) PD-1 antagonist + IL-15 + IL-21 + GITR-agonist (WIOG). Following validation of TIL purity and activation phenotypes by flow cytometry, RNA sequencing was performed to elucidate the underlying mechanisms. In vitro efficacy was assessed using a 7-AAD/Far-Red cytotoxicity assay against autologous tumor cells, and in vivo efficacy was evaluated in NSG mice bearing subcutaneous patient-derived tumor cell xenografts (PDCX). Results: On day 14, the WIOG group showed a 1.3-fold increase in expansion compared to the control group, along with a high CD8+/Treg ratio (454.6). Furthermore, both CD8⁺ and CD4⁺ T cells in the WIOG group exhibited elevated Granzyme B expression. RNA sequencing identified 279 upregulated genes associated with T cell activation (CSF2, TNFRSF4), cytotoxicity (IFNG, GZMB), and anti-apoptosis (BMF, BCL2L1). Compared to the controls, the WIOG group demonstrated a 1.9-fold increase in cytolytic activity in vitro and a 56% reduction in tumor growth in the patient-derived tumor cell xenograft (PDCX) model. Conclusions: Taken together, we demonstrated that the addition of an agonistic GITR antibody during the early phase of TIL culture increased the CD8⁺ T cell to Treg cell ratio and enhanced anti-tumor T cell immunity. Enhancing TILs with a GITR agonist may be beneficial for improving the clinical outcomes of TIL-based ACT in OC.
Keywords: Tumor-infiltrating lymphocytes, T cell expansion, GITR, ovarian cancer, Cancerimmunotherapy, PdCx
Received: 22 Jul 2025; Accepted: 23 Oct 2025.
Copyright: © 2025 Jung, Goh, Kim, Lee, Lee, Hwanga, Kang, Park and An. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Hee-Jung An, hjahn@cha.ac.kr
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