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

Revach, O.-Y.; Cicerchia, A. M.; Shorer, O.; Petrova, B.; Anderson, S.; Park, J.; Chen, L.; Mehta, A.; Wright, S. J.; McNamee, N.; Tal-Mason, A.; Cattaneo, G.; Tiwari, P.; Xie, H.; Sweere, J. M.; Cheng, L.-C.; Sigal, N.; Enrico, E.; Miljkovic, M.; Evans, S. A.; Nguyen, N.; Whidden, M. E.; Srinivasan, R.; Spitzer, M. H.; Sun, Y.; Sharova, T.; Lawless, A.; Michaud, W. A.; Rasmussen, M. Q.; Fang, J.; Palin, C.; Chen, F.; Wang, X.; Ferrone, C. R.; Lawrence, D. P.; Sullivan, R. J.; Liu, D.; Sachdeva, U. M.; Sen, D. R.; Flaherty, K. T.; Manguso, R. T.; Bod, L.; Kellis, M.; Boland, G. M.; Yizhak, K.

doi:10.1101/2024.02.12.579184

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bioRxiv · 10.1101/2024.02.12.579184

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

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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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Revach, O.-Y., Cicerchia, A. M., Shorer, O., Petrova, B., Anderson, S., Park, J., Chen, L., Mehta, A., Wright, S. J., McNamee, N., Tal-Mason, A., Cattaneo, G., Tiwari, P., Xie, H., Sweere, J. M., Cheng, L.-C., Sigal, N., Enrico, E., Miljkovic, M., Evans, S. A., Nguyen, N., Whidden, M. E., Srinivasan, R., Spitzer, M. H., Sun, Y., Sharova, T., Lawless, A., Michaud, W. A., Rasmussen, M. Q., Fang, J., Palin, C., Chen, F., Wang, X., Ferrone, C. R., Lawrence, D. P., Sullivan, R. J., Liu, D., Sachdeva, U. M., Sen, D. R., Flaherty, K. T., Manguso, R. T., Bod, L., Kellis, M., Boland, G. M., Yizhak, K.. 2024-02-14. Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy. https://doi.org/10.1101/2024.02.12.579184

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