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

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 health...

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Vydáno v:Proceedings of the National Academy of Sciences - PNAS Ročník 122; číslo 39; s. e2419888122
Hlavní autoři: Alencar, Gabriel F, Mohamed, Asmaa O, Burnett, Madison G, Jean, Samantha St, Nelson, Anders R, Su, Yapeng, Voillet, Valentin, Bates, Breanna M, Rodgers Suarez, Magdalia, Ruskin, Susan L, Trieu, Lam, Lam, Jennifer L, Bekiranov, Stefan, Gottardo, Raphael, Greenberg, Philip D, Anderson, Kristin G
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 30.09.2025
Témata:
Animals
Antigens, CD - genetics
Antigens, CD - immunology
Antigens, CD - metabolism
Cell Line, Tumor
Disease Models, Animal
Female
Hepatitis A Virus Cellular Receptor 2 - antagonists & inhibitors
Hepatitis A Virus Cellular Receptor 2 - immunology
Hepatitis A Virus Cellular Receptor 2 - metabolism
Humans
Immune Checkpoint Inhibitors - pharmacology
Immunotherapy, Adoptive - methods
Lymphocyte Activation Gene 3 Protein
Mesothelin
Mice
Ovarian Neoplasms - genetics
Ovarian Neoplasms - immunology
Ovarian Neoplasms - pathology
Ovarian Neoplasms - therapy
Programmed Cell Death 1 Receptor - antagonists & inhibitors
Programmed Cell Death 1 Receptor - immunology
T-Lymphocytes - immunology
Tumor Microenvironment - immunology
checkpoint blockade
T cell engineering
ovarian cancer
adoptive cell therapy
immunotherapy
ISSN:1091-6490, 1091-6490
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Shrnutí: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 (TCR ) 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 TCR with singlet or doublet antibody combinations. Single-cell RNA sequencing revealed TCR 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.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.2419888122