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 |
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| Hlavní autoři: | , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
30.09.2025
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| ISSN: | 1091-6490, 1091-6490 |
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| Abstract | 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. |
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| AbstractList | 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. 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.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. |
| Author | Jean, Samantha St Alencar, Gabriel F Ruskin, Susan L Lam, Jennifer L Bates, Breanna M Bekiranov, Stefan Rodgers Suarez, Magdalia Anderson, Kristin G Trieu, Lam Su, Yapeng Burnett, Madison G Gottardo, Raphael Voillet, Valentin Nelson, Anders R Greenberg, Philip D Mohamed, Asmaa O |
| Author_xml | – sequence: 1 givenname: Gabriel F surname: Alencar fullname: Alencar, Gabriel F organization: Department of Microbiology, Immunology and Cancer Biology, and Beirne B. Carter Center for Immunology Research University of Virginia School of Medicine, Charlottesville, VA 22908 – sequence: 2 givenname: Asmaa O surname: Mohamed fullname: Mohamed, Asmaa O organization: Department of Microbiology, Immunology and Cancer Biology, and Beirne B. Carter Center for Immunology Research University of Virginia School of Medicine, Charlottesville, VA 22908 – sequence: 3 givenname: Madison G orcidid: 0000-0003-4852-3639 surname: Burnett fullname: Burnett, Madison G organization: Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 – sequence: 4 givenname: Samantha St orcidid: 0000-0001-5555-9299 surname: Jean fullname: Jean, Samantha St organization: Department of Pathology and Center for Comparative Medicine, University of Virginia, Charlottesville, VA 22908 – sequence: 5 givenname: Anders R surname: Nelson fullname: Nelson, Anders R organization: Department of Microbiology, Immunology and Cancer Biology, and Beirne B. Carter Center for Immunology Research University of Virginia School of Medicine, Charlottesville, VA 22908 – sequence: 6 givenname: Yapeng surname: Su fullname: Su, Yapeng organization: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109 – sequence: 7 givenname: Valentin orcidid: 0000-0002-5751-3881 surname: Voillet fullname: Voillet, Valentin organization: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109 – sequence: 8 givenname: Breanna M surname: Bates fullname: Bates, Breanna M organization: Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 – sequence: 9 givenname: Magdalia surname: Rodgers Suarez fullname: Rodgers Suarez, Magdalia organization: Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 – sequence: 10 givenname: Susan L orcidid: 0009-0005-2699-7296 surname: Ruskin fullname: Ruskin, Susan L organization: Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 – sequence: 11 givenname: Lam surname: Trieu fullname: Trieu, Lam organization: Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 – sequence: 12 givenname: Jennifer L surname: Lam fullname: Lam, Jennifer L organization: Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 – sequence: 13 givenname: Stefan orcidid: 0000-0002-3177-4346 surname: Bekiranov fullname: Bekiranov, Stefan organization: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908 – sequence: 14 givenname: Raphael surname: Gottardo fullname: Gottardo, Raphael organization: Biomedical Data Science Center, Division of Clinical Research and Innovation, Lausanne University Hospital & University of Lausanne, and Swiss Institute of Bioinformatics, Lausanne 1005, Switzerland – sequence: 15 givenname: Philip D orcidid: 0000-0003-3812-647X surname: Greenberg fullname: Greenberg, Philip D organization: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109 – sequence: 16 givenname: Kristin G orcidid: 0000-0001-9263-4438 surname: Anderson fullname: Anderson, Kristin G organization: Department of Obstetrics and Gynecology, University of Virginia School of Medicine, Charlottesville, VA 22908 |
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| Title | Triple checkpoint blockade of PD-1, Tim-3, and Lag-3 enhances adoptive T cell immunotherapy in a mouse model of ovarian cancer |
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