Induction of cell death in malignant cells and regulatory T cells in the tumor microenvironment by targeting CD137

Sep 21, 2026

Uploaded by Ophelia

Regulatory T cells (Tregs) drive immunosuppression within the tumor microenvironment, limiting effectiveness of immunotherapies for solid cancers. Strategies that reduce Tregs can also harm effector T cells (Teffs), diminishing anti-tumor immunity and risking autoimmunity. CD137 is highly expressed in intratumoral Tregs across solid cancers and is also present on certain malignant cells, supporting its use as a therapeutic target.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Abstract

Introduction

Tumor microenvironment and Treg biology

CD137 as a marker and therapeutic target

ORIGINAL RESEARCH Induction of cell death in malignant cells and regulatory T cells in the tumor microenvironment by targeting CD137 Rui Suna,b,c,d, Kang Yi Leeb,c,e, Yu Meib,c,e, Emily Nicklesa,b,c, Jia Le Lina,b,c, Runze Xiaa,b,c,d, Haiyan Liub,c,e, and Herbert Schwarz a,b,c,d aDepartment of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; bNUS Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore; cNUSMED Immunology Translational Research Programme, National University of Singapore, Singapore, Singapore; dIntegrative Sciences and Engineering Programme, National University of Singapore, Singapore, Singapore; e Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore ABSTRACT Regulatory T cells (Tregs) contribute significantly to the immunosuppressive nature of the tumor microenvironment which is a main barrier for immunotherapies of solid cancers. Reducing Treg numbers enhances anti-tumor immune responses but current depletion strategies also impair effector T cells (Teffs), potentially leading to reduced anti-tumor immunity and/or autoimmune diseases. CD137 has been identified as the most differentially expressed gene between peripheral Tregs and intratumoral Tregs in virtually all solid cancers. Further, CD137 is expressed by malignant cells of certain cancers, making it a potential target for tumor immunotherapy. Here, we report the development of a fully human anti-human CD137 antibody of the IgG1 isotype, clone P1A1, that induces antibody-dependent cellmediated cytotoxicity (ADCC) in CD137+ Tregs and cancer cells. P1A1 cross-reacts with murine CD137 which allowed testing murine chimeric P1A1 in syngeneic murine tumor models where P1A1 significantly reduced the number of CD137+ Tregs and inhibited tumor growth in a murine hepatocellular carcinoma (HCC) and a melanoma lung metastasis model. P1A1 can also be internalized thus enabling it as a carrier for drugs to target CD137+ Tregs and cancer cells. These anti-cancer properties suggest a translation of P1A1 to human immunotherapy. ARTICLE HISTORY Received 21 October 2024 Revised 11 December 2024 Accepted 11 December 2024 KEYWORDS Antibody; CD137; depletion; regulatory T cell; tumor microenvironment Introduction The immunosuppressive tumor microenvironment (TME) isone of the main barriers for effective immunotherapies for solid tumors. Foxp3+CD25+CD4+ regulatory T cells (Tregs) are among the suppressor cells and play a vital role in hampering anti-tumor responses. Tregs abundantly infiltrate into tumor tissues, and a high abundance of infiltrated Tregs is associated with poor clinical outcomes in various types of cancer. 1,2 Reducing the numbers of intratumoral Tregs by monoclonal antibodies enhances anti-tumor immunity and improves the efficacy of immunotherapy.3 Antibody-based Treg depletion is induced by the binding of the fragment crystallizable (Fc) region of the antibody to Fcγ receptors (FcγR) on immune cells, including NK cells and phagocytes, to trigger antibody dependent cell-mediated cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) against target cells. Recently, CD137 has been identified as a signature marker for intratumoral Tregs. Human and murine Tregs that had infiltrated tumors expressed high amounts of CD137,4 while peripheral Treg had low to negligible levels.5,6 A high frequency of CD137+ Treg correlated with poor prognosis in lung adenocarcinoma patients.7 This is in line with CD137+ Treg having been more suppressive than CD137 − Treg.8 This association of CD137 with Treg and immunosuppression is surprising since CD137 is best known as a potent T cell costimulatory molecule. CD137 signaling enhances T cell survival and proliferation, IFN-γ secretion and cytotoxicity of Teffs,9, 10 and is a potent driver for T helper type 1 (Th1)/ T

FAQs

Why are regulatory T cells important in solid tumor immunosuppression?

Regulatory T cells contribute to the immunosuppressive tumor microenvironment and hinder effective anti-tumor immune responses.

What limitation do current Treg depletion strategies have?

They can reduce Treg numbers but may also impair effector T cells, potentially lowering anti-tumor immunity and increasing risk of autoimmune diseases.

How does targeting CD137 relate to both Tregs and cancer cells?

CD137 is identified as a signature marker for intratumoral Tregs and can also be expressed by malignant cells in certain cancers, making CD137 a potential immunotherapy target.

Sep 21, 2026

Uploaded by Ophelia