Research Spotlight: Key Insights into the Roles and Regulation of CD38 in T Cell Dysfunction

Or-Yam Revach, PhD, a postdoctoral research fellow, and Russell W. Jenkins, MD, PhD, a physician-investigator in the Mass General Cancer Center, are the lead and senior authors, respectively, of a paper published in Cell Reports Medicine, “Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants.”

Q: How would you summarize your study for a lay audience?

While outcomes for patients with advanced melanoma have significantly improved over the last decade due to advances in cancer immunotherapy, roughly half of patients with advanced melanoma do not benefit from existing immunotherapy treatments.

CD8+ tumor-infiltrating lymphocytes (TILs) are potent cancer-fighting immune cells that are critically important for eradicating tumors and are the prime target of existing cancer immunotherapy treatments. However, CD8+ TILs can become dysfunctional in the hostile tumor microenvironment, after which they lose the capacity to kill cancer cells.

In our study, we demonstrated that a specific molecule, CD38, is highly upregulated in dysfunctional CD8+ T cells and is increased in CD8+ T cells from melanoma patients resistant to cancer immunotherapy.

We confirmed that high levels of CD38 disturb metabolism in CD8+ TILs, robbing them of key factors needed to fight cancer.

Disrupting the function of CD38 corrected these metabolic issues and combining drugs targeting CD38 with existing cancer immunotherapy resulted in improved control of tumors in cells from patients resistant to anti-PD-1 immune checkpoint blockade cancer immunotherapy.

Q: What question were you investigating?

Previous studies have observed associations between high levels of CD38 in T cells and decreased response to immunotherapy, as well as favorable effects of disrupting CD38 in mouse models of cancer.

However, the specific role of CD38 in driving resistance to immunotherapy in melanoma, as well as the impact of combining CD38 targeting with existing immunotherapy drugs using patient-derived tumor models of human cancer were yet to be determined.

Ultimately, we wanted to determine whether disrupting CD38 would restore sensitivity to cancer immunotherapy in pre-clinical models of human tumor immunity.

Q: What methods or approaches did you use?

A key distinguishing feature of our study was the intense focus on using clinically relevant data and specimens, in addition to more traditional mouse models.

We leveraged established and novel single-cell RNA sequencing, mass cytometry of peripheral immune cells, and plasma proteomics from patients with melanoma to confirm the association between high levels of CD38 and clinical resistance to anti-PD-1 immune checkpoint blockade cancer immunotherapy.

To validate these findings, we used a suite of model systems to examine the T cell-specific role(s) of CD38, as well as more sophisticated three-dimensional cultures of patient-derived organotypic tumor spheroids (PDOTS).

PDOTS are tumor biopsies that retain autologous tumor-infiltrating immune and stromal cells and can be used in ex vivo 3D microfluidic culture and drug sensitivity testing.

Q: What did you find?

We found CD38+CD8+ TILs accumulate specifically in tumors and exhibit features of T cell dysfunction, including low expression of the transcription factor TCF7, decreased proliferative capacity, and altered mitochondrial bioenergetics.

Genetic disruption of CD38 limits the development of these functional and metabolic defects, resulting in improved T cell function, and restored sensitivity to cancer immunotherapy in patient tumors with clinical resistance to the existing treatment of targeting the PD-1 immune checkpoint.

We observed restoration of T cell function by disrupting CD38 function in TILs as well as chimeric antigen receptor (CAR) T-cells.

Lastly, we demonstrated that dual PD-1/CD38 blockade was able to overcome cancer immunotherapy resistance.

Q: What are the implications?

Our findings provide key insights into the roles and regulation of CD38 in T cell dysfunction and demonstrate the therapeutic potential of disrupting CD38 function to restore sensitivity to cancer immunotherapy in melanoma.

Q: What are the next steps?

Given the availability of FDA-approved monoclonal antibodies targeting CD38, there is great interest in leveraging these findings into a clinical trial combining PD-1 blockade cancer immunotherapy with anti-CD38 antibodies in melanoma.

Authorship: In addition to Revach and Jenkins, Mass General Brigham authors include Angelina M. Cicerchia, Claire A. Palin, Seth Anderson, Arnav Mehta, Niamh McNamee, Aya Tal-Mason, Giulia Cattaneo, Hongyan Xie, Yi Sun, Tatyana Sharova, Aleigha R. Lawless, William A. Michaud, Michaud Q. Rasmussen, Jacy Fang, Feng Chen, Xinhui Wang, Donald P. Lawrence, Ryan J. Sullivan, Uma M. Sachdeva, Debattama R. Sen, Keith T. Flaherty, Robert T. Manguso, Lloyd Bod, Genevieve M. Boland, Moshe Sade-Feldman, and Nir Hacohen.

Paper cited: Revach O., et al. “Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants.” Cell Reports Medicine. DOI: 10.1158/1538-7445.GENFUNC25-B034

Funding: This work was supported by a V Foundation Translational Research Grant.

Disclosures: Jenkins is a member of the advisory board and has a financial interest in Xsphera Biosciences Inc.