Summary of project PR002357
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002357. The data can be accessed directly via it's Project DOI: 10.21228/M8ZN7S This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR002357 |
| Project DOI: | doi: 10.21228/M8ZN7S |
| Project Title: | Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants |
| Project Summary: | T cell exhaustion is a major driver of immune checkpoint blockade (ICB) resistance and clinically effective strategies to prevent or reverse itT cell exhaustion to restore ICB sensitivity are lacking. CD38, an ecto-enzyme involved in NAD+ catabolism, is highly expressed in exhausted CD8+ T cells in human melanoma, yet its role in T cell exhaustion remains to be elucidated. Here we show that CD38+CD8+ T cells are enriched during tumor progression and are strongly associated with ICB resistance in melanoma. Chronic TCR activation and type I interferon stimulation upregulate CD38 in human T cells, leading to mitochondrial dysfunction and reduced anti-tumor activity. Disrupting CD38 restored cellular NAD+ pools and T cell bioenergetics, leading to increased TCF7 expression, improved T cell proliferation, and enhanced effector function. Importantly, targeting CD38 in a cohort of patient-derived organotypic tumor spheroid (PDOTS), human living tumor explants, demonstrates that CD38-directed therapies can overcome ICB resistance in clinically resistant human melanoma, an effect that is furthered induced by supplementation with NAD+. These results emphasize the need for further preclinical and clinical evaluation of CD38 directed therapies in melanoma and underscore the importance of NAD+ as a vital metabolite to enhance those therapies. |
| Institute: | Massachusetts General Hospital |
| Department: | KF-CCR |
| Laboratory: | Jenkins lab |
| Last Name: | Revach |
| First Name: | Or-Yam |
| Address: | 55 Fruit street, Boston, MA, 02114, USA |
| Email: | oryamush@gmail.com |
| Phone: | (617) 726-5130 |
Summary of all studies in project PR002357
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST003779 | Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants - Intracellular metabolomics of B7.H3 human CAR-T cells | Homo sapiens | Massachusetts General Hospital | MS | 2025-05-14 | 1 | 15 | Uploaded data (2.1G)* |
| ST003830 | Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants - Extracellular metabolomics of B7.H3 human CAR-T cells | Homo sapiens | Massachusetts General Hospital | MS | 2025-05-14 | 1 | 27 | Uploaded data (3.3G)* |
