High CD38 expression defines a mitochondrial function adapted CD8 + T cell subset with implications for lung cancer immunotherapy

Abstract Despite identifying specific CD8⁺T cell subsets associated with immunotherapy resistance, the molecular pathway triggering the process remains elusive. Given the potential of CD38 in regulating CD8⁺T cell function, we aimed to observe the accumulation of CD38⁺CD8⁺T cells in lung cancer and further explored its role in immunotherapy resistance. Phenotypic analysis of tumoral CD8⁺T cells from both lung cancer patients and immunotherapy-resistant pre-clinical models identifies that CD38-expressing CD8⁺T cells displayed as CD38hi and CD38intT cell subsets. Following, it was observed a higher expression of CD38 along with T cell exhaustion genes and dysregulated mitochondrial bioenergetics. In addition, it was suggested that an evaluated CD38hiCD8⁺T cells in peripheral but not in center of TME were associated with good response to anti-PD-1 therapy in NSCLC, as well as corresponding depth of clinical regression, which was evidenced by more depletion of CD38hiCD8⁺T cells occur in subject with higher regional CD38hiCD8⁺T cells infiltration. As expected, it was found that ICIs-resistant murine lung cancer models had lack of effective reduction in term of CD38hiCD8⁺T cells when receiving PD-L1 mAb alone. Notably, combination therapy of PD-L1 mAb and EGCG could selectively restrict CD38hiCD8⁺T cells infiltration and enhance IFN-γ production by these T cells, thereby significantly improved survival in this carcinoma model. This restored immunotherapy sensitivity was found to be related to the selective improved mitochondrial of CD38hiCD8⁺T cells, which was validated by the established link between IFN-γ production and mitochondrial metabolism. Collectively, our data highlighted a role for the CD38-coupled dysfunctional mitochondrial in promoting CD8⁺T cell exhaustion and intrinsic resistance to ICIs therapy, thereby offered a rationale target to enhance the therapeutic efficacy of PD-1 blockade therapy in lung cancer.