Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy

Or-Yam Revach; Angelina M Cicerchia; Ofir Shorer; Boryana Petrova; Seth Anderson; Joshua Park; Lee Chen; Arnav Mehta; Samuel J Wright; Niamh McNamee; Aya Tal-Mason; Giulia Cattaneo; Payal Tiwari; Hongyan Xie; Johanna M Sweere; Li-Chun Cheng; Natalia Sigal; Elizabeth Enrico; Marisa Miljkovic; Shane A Evans; Ngan Nguyen; Mark E Whidden; Ramji Srinivasan; Matthew H Spitzer; Yi Sun; Tatyana Sharova; Aleigha R Lawless; William A Michaud; Martin Q Rasmussen; Jacy Fang; Claire A Palin; Feng Chen; Xinhui Wang; Cristina R Ferrone; Donald P Lawrence; Ryan J Sullivan; David Liu; Uma M Sachdeva; Debattama R Sen; Keith T Flaherty; Robert T Manguso; Lloyd Bod; Manolis Kellis; Genevieve M Boland; Keren Yizhak; Jiekun Yang; Naama Kanarek; Moshe Sade-Feldman; Nir Hacohen; Russell W Jenkins

doi:10.1101/2024.02.12.579184

Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy

bioRxiv [Preprint]. 2024 Mar 26:2024.02.12.579184. doi: 10.1101/2024.02.12.579184.

Authors

Or-Yam Revach^{1

2

3}, Angelina M Cicerchia¹, Ofir Shorer⁴, Boryana Petrova^{2

5}, Seth Anderson^{1

3}, Joshua Park³, Lee Chen⁶, Arnav Mehta^{1

2

3}, Samuel J Wright³, Niamh McNamee^{2

7}, Aya Tal-Mason^{2

7}, Giulia Cattaneo⁸, Payal Tiwari³, Hongyan Xie^{1

2

3}, Johanna M Sweere⁹, Li-Chun Cheng⁹, Natalia Sigal⁹, Elizabeth Enrico⁹, Marisa Miljkovic⁹, Shane A Evans⁹, Ngan Nguyen⁹, Mark E Whidden⁹, Ramji Srinivasan⁹, Matthew H Spitzer^{9

10

11

12

13}, Yi Sun¹, Tatyana Sharova⁸, Aleigha R Lawless⁸, William A Michaud⁸, Martin Q Rasmussen^{1

3}, Jacy Fang^{1

3}, Claire A Palin¹, Feng Chen⁸, Xinhui Wang^{2

8}, Cristina R Ferrone^{2

8

14}, Donald P Lawrence^{1

2}, Ryan J Sullivan^{1

2}, David Liu^{2

3

15}, Uma M Sachdeva^{2

7}, Debattama R Sen^{1

2

3}, Keith T Flaherty^{1

2}, Robert T Manguso^{1

2

3}, Lloyd Bod^{1

2

3}, Manolis Kellis⁵, Genevieve M Boland^{2

3

8}, Keren Yizhak⁴, Jiekun Yang⁶, Naama Kanarek^{2

3

5}, Moshe Sade-Feldman^{1

2

3}, Nir Hacohen^{1

2

3}, Russell W Jenkins^{1

2

3}

Affiliations

¹ Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
² Harvard Medical School, Boston, MA, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
⁵ Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
⁶ Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁷ Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA, USA.
⁸ Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
⁹ Teiko Bio, Salt Lake City, UT, USA.
¹⁰ Department of Otolaryngology-Head and Neck Cancer, University of California, San Francisco, San Francisco, CA, USA.
¹¹ Department of Microbiology & Immunology, University of California, San Francisco, San Francisco, CA, USA.
¹² Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
¹³ Chan Zuckerberg Biohub, San Francisco, CA 94158; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
¹⁴ Department of Surgery, Cedars-Sinai Medical Center Los Angeles, CA, USA.
¹⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Abstract

A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma^1,2. 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 CD38^hiCD8⁺ 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.

Keywords: 3D microfluidic culture; CD38; NAD+; PD-1; T cell exhaustion; cytokines; immunotherapy; organotypic tumour spheroids.

Publication types

Preprint

Abstract

Publication types

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