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Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade.
Palmer, Douglas C; Webber, Beau R; Patel, Yogin; Johnson, Matthew J; Kariya, Christine M; Lahr, Walker S; Parkhurst, Maria R; Gartner, Jared J; Prickett, Todd D; Lowery, Frank J; Kishton, Rigel J; Gurusamy, Devikala; Franco, Zulmarie; Vodnala, Suman K; Diers, Miechaleen D; Wolf, Natalie K; Slipek, Nicholas J; McKenna, David H; Sumstad, Darin; Viney, Lydia; Henley, Tom; Bürckstümmer, Tilmann; Baker, Oliver; Hu, Ying; Yan, Chunhua; Meerzaman, Daoud; Padhan, Kartik; Lo, Winnie; Malekzadeh, Parisa; Jia, Li; Deniger, Drew C; Patel, Shashank J; Robbins, Paul F; McIvor, R Scott; Choudhry, Modassir; Rosenberg, Steven A; Moriarity, Branden S; Restifo, Nicholas P.
Afiliación
  • Palmer DC; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA. Electronic address: palmerdc33@gmail.com.
  • Webber BR; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA. Electronic address: webb0178@umn.edu.
  • Patel Y; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA.
  • Johnson MJ; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.
  • Kariya CM; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA.
  • Lahr WS; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.
  • Parkhurst MR; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA.
  • Gartner JJ; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA.
  • Prickett TD; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA.
  • Lowery FJ; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA.
  • Kishton RJ; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA.
  • Gurusamy D; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA.
  • Franco Z; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA.
  • Vodnala SK; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA.
  • Diers MD; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.
  • Wolf NK; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.
  • Slipek NJ; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.
  • McKenna DH; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
  • Sumstad D; Molecular and Cellular Therapeutics, University of Minnesota, Saint Paul, MN, USA.
  • Viney L; Intima Bioscience, Inc., New York, NY, USA.
  • Henley T; Intima Bioscience, Inc., New York, NY, USA.
  • Bürckstümmer T; Intima Bioscience, Inc., New York, NY, USA.
  • Baker O; Intima Bioscience, Inc., New York, NY, USA.
  • Hu Y; The Center for Biomedical Informatics and Information Technology (CBIIT), National Institutes of Health, Bethesda, MD, USA.
  • Yan C; The Center for Biomedical Informatics and Information Technology (CBIIT), National Institutes of Health, Bethesda, MD, USA.
  • Meerzaman D; The Center for Biomedical Informatics and Information Technology (CBIIT), National Institutes of Health, Bethesda, MD, USA.
  • Padhan K; National Institute of Allergy and Infectious Disease (NIAID), National Institutes of Health, Bethesda, MD, USA.
  • Lo W; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA.
  • Malekzadeh P; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA.
  • Jia L; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA.
  • Deniger DC; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA.
  • Patel SJ; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA.
  • Robbins PF; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA.
  • McIvor RS; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA; Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA.
  • Choudhry M; Intima Bioscience, Inc., New York, NY, USA.
  • Rosenberg SA; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA. Electronic address: sar@nih.gov.
  • Moriarity BS; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA. Electronic address: mori0164@umn.edu.
  • Restifo NP; Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, USA. Electronic address: restifon@mail.nih.gov.
Med ; 3(10): 682-704.e8, 2022 10 14.
Article en En | MEDLINE | ID: mdl-36007524
ABSTRACT

BACKGROUND:

Adoptive transfer of tumor-infiltrating lymphocytes (TIL) fails to consistently elicit tumor rejection. Manipulation of intrinsic factors that inhibit T cell effector function and neoantigen recognition may therefore improve TIL therapy outcomes. We previously identified the cytokine-induced SH2 protein (CISH) as a key regulator of T cell functional avidity in mice. Here, we investigate the mechanistic role of CISH in regulating human T cell effector function in solid tumors and demonstrate that CRISPR/Cas9 disruption of CISH enhances TIL neoantigen recognition and response to checkpoint blockade.

METHODS:

Single-cell gene expression profiling was used to identify a negative correlation between high CISH expression and TIL activation in patient-derived TIL. A GMP-compliant CRISPR/Cas9 gene editing process was developed to assess the impact of CISH disruption on the molecular and functional phenotype of human peripheral blood T cells and TIL. Tumor-specific T cells with disrupted Cish function were adoptively transferred into tumor-bearing mice and evaluated for efficacy with or without checkpoint blockade.

FINDINGS:

CISH expression was associated with T cell dysfunction. CISH deletion using CRISPR/Cas9 resulted in hyper-activation and improved functional avidity against tumor-derived neoantigens without perturbing T cell maturation. Cish knockout resulted in increased susceptibility to checkpoint blockade in vivo.

CONCLUSIONS:

CISH negatively regulates human T cell effector function, and its genetic disruption offers a novel avenue to improve the therapeutic efficacy of adoptive TIL therapy.

FUNDING:

This study was funded by Intima Bioscience, U.S. and in part through the Intramural program CCR at the National Cancer Institute.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T / Linfocitos Infiltrantes de Tumor Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Med Año: 2022 Tipo del documento: Article
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T / Linfocitos Infiltrantes de Tumor Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Med Año: 2022 Tipo del documento: Article