Triple checkpoint blockade of PD-1, Tim-3, and Lag-3 enhances adoptive T cell immunotherapy in a mouse model of ovarian cancer

• 成果类型: Article
• 署名作者: Alencar, Gabriel F.; Mohamed, Asmaa O.; Burnett, Madison G.; St Jean, Samantha; Nelson, Anders R.; Su, Yapeng; Voillet, Valentin; Bates, Breanna M.; Suarez, Magdalia Rodgers; Ruskin, Susan L.; Trieu, Lam; Lam, Jennifer L.; Bekiranov, Stefan; Gottardo, Raphael; Greenberg, Philip D.; Anderson, Kristin G.
• 署名单位: University of Virginia; University of Virginia; Fred Hutchinson Cancer Center; University of Virginia; University of Virginia; University of Washington; University of Washington Seattle; Fred Hutchinson Cancer Center; University of Virginia; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); University of Lausanne; Swiss Institute of Bioinformatics; University of Virginia
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12160
• DOI: 10.1073/pnas.2419888122
• 发表日期: 2025-09-30
• 关键词: effector; receptor; antigen

摘要

The five-year survival rate for ovarian cancer patients remains below 50%, underscoring the need for innovative therapies. One promising approach involves engineering T cells to specifically target proteins uniquely overexpressed in tumors, thereby controlling tumor growth without toxicity to healthy tissues. Mesothelin (MSLN) contributes to the malignant and invasive phenotype in ovarian cancer and has limited expression in healthy cells, making it a candidate immunotherapy target. Our previous results in a mouse model of ovarian cancer demonstrated that T cells engineered to express a T cell receptor (TCR) targeting MSLN (TCRMSLN) mediated therapeutic activity, delaying tumor growth and prolonging mouse survival. However, inhibitory ligands expressed in the tumor microenvironment (TME) interacted with inhibitory receptors on activated T cells, suppressing antitumor function. We hypothesized combining engineered T cells with checkpoint blockade would enhance T cell function and improve therapeutic efficacy, but administration of monospecific antibodies targeting individual inhibitory pathways had no significant impact on T cell efficacy. By contrast, the combination of PD-1, Tim-3, and Lag-3 blockade with engineered T cells significantly improved T cell function and overall animal survival relative to treatment with antibody alone or TCRMSLN with singlet or doublet antibody combinations. Single-cell RNA sequencing revealed TCRMSLN T cells treated with the triplet antibody combination increased expression of genes involved in interferon responses and metabolic function, and reduced expression of genes associated with exhaustion. These results suggest that strategies to disrupt multiple inhibitory pathways simultaneously may be necessary for improved adoptive T cell therapy efficacy in patients.