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Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy.
Revach, Or-Yam; Cicerchia, Angelina M; Shorer, Ofir; Petrova, Boryana; Anderson, Seth; Park, Joshua; Chen, Lee; Mehta, Arnav; Wright, Samuel J; McNamee, Niamh; Tal-Mason, Aya; Cattaneo, Giulia; Tiwari, Payal; Xie, Hongyan; Sweere, Johanna M; Cheng, Li-Chun; Sigal, Natalia; Enrico, Elizabeth; Miljkovic, Marisa; Evans, Shane A; Nguyen, Ngan; Whidden, Mark E; Srinivasan, Ramji; Spitzer, Matthew H; Sun, Yi; Sharova, Tatyana; Lawless, Aleigha R; Michaud, William A; Rasmussen, Martin Q; Fang, Jacy; Palin, Claire A; Chen, Feng; Wang, Xinhui; Ferrone, Cristina R; Lawrence, Donald P; Sullivan, Ryan J; Liu, David; Sachdeva, Uma M; Sen, Debattama R; Flaherty, Keith T; Manguso, Robert T; Bod, Lloyd; Kellis, Manolis; Boland, Genevieve M; Yizhak, Keren; Yang, Jiekun; Kanarek, Naama; Sade-Feldman, Moshe; Hacohen, Nir; Jenkins, Russell W.
Afiliação
  • Revach OY; Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Cicerchia AM; Harvard Medical School, Boston, MA, USA.
  • Shorer O; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Petrova B; Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Anderson S; Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
  • Park J; Harvard Medical School, Boston, MA, USA.
  • Chen L; Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
  • Mehta A; Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Wright SJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • McNamee N; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Tal-Mason A; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Cattaneo G; Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Tiwari P; Harvard Medical School, Boston, MA, USA.
  • Xie H; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Sweere JM; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Cheng LC; Harvard Medical School, Boston, MA, USA.
  • Sigal N; Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA, USA.
  • Enrico E; Harvard Medical School, Boston, MA, USA.
  • Miljkovic M; Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA, USA.
  • Evans SA; Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
  • Nguyen N; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Whidden ME; Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Srinivasan R; Harvard Medical School, Boston, MA, USA.
  • Spitzer MH; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Sun Y; Teiko Bio, Salt Lake City, UT, USA.
  • Sharova T; Teiko Bio, Salt Lake City, UT, USA.
  • Lawless AR; Teiko Bio, Salt Lake City, UT, USA.
  • Michaud WA; Teiko Bio, Salt Lake City, UT, USA.
  • Rasmussen MQ; Teiko Bio, Salt Lake City, UT, USA.
  • Fang J; Teiko Bio, Salt Lake City, UT, USA.
  • Palin CA; Teiko Bio, Salt Lake City, UT, USA.
  • Chen F; Teiko Bio, Salt Lake City, UT, USA.
  • Wang X; Teiko Bio, Salt Lake City, UT, USA.
  • Ferrone CR; Teiko Bio, Salt Lake City, UT, USA.
  • Lawrence DP; Department of Otolaryngology-Head and Neck Cancer, University of California, San Francisco, San Francisco, CA, USA.
  • Sullivan RJ; Department of Microbiology & Immunology, University of California, San Francisco, San Francisco, CA, USA.
  • Liu D; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • Sachdeva UM; Chan Zuckerberg Biohub, San Francisco, CA 94158; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
  • Sen DR; Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Flaherty KT; Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
  • Manguso RT; Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
  • Bod L; Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
  • Kellis M; Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Boland GM; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Yizhak K; Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Yang J; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Kanarek N; Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Sade-Feldman M; Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
  • Hacohen N; Harvard Medical School, Boston, MA, USA.
  • Jenkins RW; Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
bioRxiv ; 2024 Mar 26.
Article em En | MEDLINE | ID: mdl-38405985
ABSTRACT
A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma1,2. T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance3. Here, we show that CD38, an ecto-enzyme involved in nicotinamide adenine dinucleotide (NAD+) catabolism, is highly expressed in exhausted CD8+ T cells in melanoma and is associated with ICB resistance. Tumour-derived CD38hiCD8+ T cells are dysfunctional, characterised by impaired proliferative capacity, effector function, and dysregulated mitochondrial bioenergetics. Genetic and pharmacological blockade of CD38 in murine and patient-derived organotypic tumour models (MDOTS/PDOTS) enhanced tumour immunity and overcame ICB resistance. Mechanistically, disrupting CD38 activity in T cells restored cellular NAD+ pools, improved mitochondrial function, increased proliferation, augmented effector function, and restored ICB sensitivity. Taken together, these data demonstrate a role for the CD38-NAD+ axis in promoting T cell exhaustion and ICB resistance, and establish the efficacy of CD38 directed therapeutic strategies to overcome ICB resistance using clinically relevant, patient-derived 3D tumour models.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos