A new publication by Revach et al. in Cell Reports Medicine from Massachusetts General Hospital (MGH) uncovers a key mechanism of immune checkpoint blockade (ICB) resistance in melanoma: the emergence of CD38⁺ exhausted CD8⁺ T cells post-treatment that correlates with ICB resistance.
As part of this study on CD38⁺ T cell exhaustion and ICB resistance, Teiko partnered with MGH to analyze 86 melanoma patient blood samples via mass cytometry, uncovering CD38⁺ T cell signatures tied to ICB resistance. This cytometry data revealed systemic immune features linked to anti–PD-1 resistance.
“Higher circulating levels of CD38⁺CD4⁺ T cells have been associated with diminished ICB sensitivity in melanoma. Multiplexed cytometry by time of flight (CyTOF) analysis of peripheral blood from melanoma patients (before and after initiating ICB treatment) revealed higher levels of CD38⁺CD8⁺ T cells in ICB-NR patients.”
— Revach et al., Cell Reports Medicine
The study found that elevated CD38⁺CD8⁺ T cell levels were not present at baseline, but instead emerged after ICB treatment had begun.
“In contrast to tumors, pre-treatment circulating levels of CD38⁺CD8⁺ T cells were not significantly different between responders and non-responders, whereas higher levels of CD38⁺CD8⁺ T cells were observed in post-treatment ICB-NR samples.”
— Revach et al., Cell Reports Medicine
These findings highlight a treatment-induced signature of resistance: CD38⁺ T cells expand in the peripheral blood of non-responders only after therapy begins. Teiko’s cytometry services helped reveal this change, reinforcing CD38 as both a functional marker of immune exhaustion and a potential therapeutic target in ICB-refractory melanoma.
CD38+ T cells are associated with ICB resistance in melanoma
Using single-cell RNA sequencing of tumor-infiltrating immune cells from the B16-ova murine melanoma model, researchers found that anti–PD-1 therapy selectively increased CD38 expression in terminally exhausted CD8⁺ T cells.
“CD38 expression was significantly increased only in terminal exhausted/effector CD8⁺ T cells following PD-1 blockade.”
— Revach et al., Cell Reports Medicine
CD38 expression is induced by chronic TCR stimulation and Type I IFN signaling
Using chronic TCR stimulation and IFN-β treatment in CD8⁺ TILs and B7-H3 CAR-T cells, researchers observed strong CD38 induction in exhausted T cells. IFN-β alone significantly increased CD38 expression (Figures 5C–D), and the combination with TCR activation further depleted NAD⁺, elevated mitochondrial stress, and upregulated exhaustion markers such as PD-1 and TIM-3.
“CD38 expression was highly induced following IFN-β treatment alone and was increased further when combined with TCR activation.”
— Revach et al., Cell Reports Medicine
Dual PD-1/CD38 blockade overcomes ICB resistance in PDOTS
Ex vivo profiling of melanoma-derived patient-derived tumor organoid systems (PDOTS) demonstrated that combining anti-PD-1 (pembrolizumab) with anti-CD38 (daratumumab) led to significantly improved tumor killing compared to either treatment alone. Notably, over half of the PDOTS that responded to the dual therapy showed no response to single-agent PD-1 or CD38 blockade.
“We observed a significant reduction in PDOTS viability following a dual PD-1/CD38 blockade, which demonstrated superior anti-tumor activity compared to anti–PD-1 or anti–CD38 alone.”
— Revach et al., Cell Reports Medicine
Clinical Relevance
By linking CD38⁺ T cells to immune checkpoint blockade resistance, and uncovering a therapy-induced, metabolically dysfunctional state driven by chronic stimulation and type I IFN signaling, this study positions CD38 as both a mechanistic driver of resistance and a tractable target. The findings open new translational paths to reduce immune exhaustion and improve response durability in ICB-treated patients.
Read the full study in Cell Reports Medicine: https://doi.org/10.1016/j.xcrm.2025.102210
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