المؤلفون: Shakiba, Mojdeh, Zumbo, Paul, Espinosa-Carrasco, Gabriel, Menocal, Laura, Dündar, Friederike, Carson, Sandra E, Bruno, Emmanuel M, Sanchez-Rivera, Francisco J, Lowe, Scott W, Camara, Steven, Koche, Richard P, Reuter, Vincent P, Socci, Nicholas D, Whitlock, Benjamin, Tamzalit, Fella, Huse, Morgan, Hellmann, Matthew D, Wells, Daniel K, Defranoux, Nadine A, Betel, Doron, Philip, Mary, Schietinger, Andrea

مصطلحات موضوعية: cancer, T cells

الوصف: T cell receptor (TCR) signal strength is a key determinant of T cell responses. We developed a cancer mouse model in which tumor-specific CD8 T cells (TST cells) encounter tumor antigens with varying TCR signal strength. High-signal-strength interactions caused TST cells to up-regulate inhibitory receptors (IRs), lose effector function, and establish a dysfunction-associated molecular program. TST cells undergoing low-signal-strength interactions also up-regulated IRs, including PD1, but retained a cell-intrinsic functional state. Surprisingly, neither high- nor low-signal-strength interactions led to tumor control in vivo, revealing two distinct mechanisms by which PD1hi TST cells permit tumor escape; high signal strength drives dysfunction, while low signal strength results in functional inertness, where the signal strength is too low to mediate effective cancer cell killing by functional TST cells. CRISPR-Cas9-mediated fine-tuning of signal strength to an intermediate range improved anti-tumor activity in vivo. Our study defines the role of TCR signal strength in TST cell function, with important implications for T cell-based cancer immunotherapies.

وصف الملف: application/pdf

العلاقة: http://repository.cshl.edu/id/eprint/40480/1/2021.Shakiba.TCR.pdfTest; Shakiba, Mojdeh, Zumbo, Paul, Espinosa-Carrasco, Gabriel, Menocal, Laura, Dündar, Friederike, Carson, Sandra E, Bruno, Emmanuel M, Sanchez-Rivera, Francisco J, Lowe, Scott W, Camara, Steven, Koche, Richard P, Reuter, Vincent P, Socci, Nicholas D, Whitlock, Benjamin, Tamzalit, Fella, Huse, Morgan, Hellmann, Matthew D, Wells, Daniel K, Defranoux, Nadine A, Betel, Doron, Philip, Mary, Schietinger, Andrea (February 2022) TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion. Journal of Experimental Medicine, 219 (2). ISSN 0022-1007

الإتاحة: https://doi.org/10.1084/jem.20201966Test
http://repository.cshl.edu/id/eprint/40480Test/
http://repository.cshl.edu/id/eprint/40480/1/2021.Shakiba.TCR.pdfTest
https://www.ncbi.nlm.nih.gov/pubmed/34935874Test

المؤلفون: Shakiba, Mojdeh, Zumbo, Paul, Espinosa-Carrasco, Gabriel, Menocal, Laura, Dündar, Friederike, Carson, Sandra E., Bruno, Emmanuel M., Sanchez-Rivera, Francisco J., Lowe, Scott W., Camara, Steven, Koche, Richard P., Reuter, Vincent P., Socci, Nicholas D., Whitlock, Benjamin, Tamzalit, Fella, Huse, Morgan, Hellmann, Matthew D., Wells, Daniel K., Defranoux, Nadine A., Betel, Doron, Philip, Mary, Schietinger, Andrea

المساهمون: National Institutes of Health, National Cancer Institute, V Foundation for Cancer Research, Josie Robertson Young Investigator Award, Cancer Research Institute, Pershing Square Foundation, Weill Cornell Medicine Core Laboratories Center, U.S. Department of Defense, Serodino Family Adventure Allee Fund, Damon Runyon Cancer Research Foundation, Parker Institute for Cancer Immunotherapy, Cycle for Survival, Marie-Josée and Henry R. Kravis Center for Molecular Oncology

المصدر: Journal of Experimental Medicine ; volume 219, issue 2 ; ISSN 0022-1007 1540-9538

الوصف: T cell receptor (TCR) signal strength is a key determinant of T cell responses. We developed a cancer mouse model in which tumor-specific CD8 T cells (TST cells) encounter tumor antigens with varying TCR signal strength. High-signal-strength interactions caused TST cells to up-regulate inhibitory receptors (IRs), lose effector function, and establish a dysfunction-associated molecular program. TST cells undergoing low-signal-strength interactions also up-regulated IRs, including PD1, but retained a cell-intrinsic functional state. Surprisingly, neither high- nor low-signal-strength interactions led to tumor control in vivo, revealing two distinct mechanisms by which PD1hi TST cells permit tumor escape; high signal strength drives dysfunction, while low signal strength results in functional inertness, where the signal strength is too low to mediate effective cancer cell killing by functional TST cells. CRISPR-Cas9–mediated fine-tuning of signal strength to an intermediate range improved anti-tumor activity in vivo. Our study defines the role of TCR signal strength in TST cell function, with important implications for T cell–based cancer immunotherapies.

الإتاحة: https://doi.org/10.1084/jem.20201966Test