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Background Gastric cancer (GC) is a major health problem both in China and globally. Despite the progress in cancer immunotherapy, the response rate of PD-1 inhibitor is still far from satisfactory in GC, indicating additional nonredundant pathways might attenuate anti-tumor immunity. C-C motif chemokine receptor 8 (CCR8) is considered as a potential immunotherapeutic target in several malignancies. However, the role and clinical significance of CCR8 in GC still remains unclear.Methods This study enrolled 7 independent cohorts with 968 GC patients. Expression of CCR8 in regulatory T (Treg) cells was verified by multiplex immunofluorescence (MxIF) and flow cytometry/intracellular staining for flow cytometry (FC/ICFC). The prognostic and predictive significance of intratumoral CCR8 + Treg cell infiltration was investigated. Phenotype of tumor-infiltrating CCR8+ Treg cells was inspected by fluorescence-activated cell sorting (FACS) combined with smart-seq2, and validated by FC/ICFC. Association between intratumoral CCR8+ Treg cell infiltration and immune contexture was detected by CIBERSORTx and verified with MxIF. Moreover, an ex vivo tumor fragment model unveiled the immunosuppression of tumor-infiltrating CCR8+ Treg cells on CD8+ T cells, and interventional experiments examined the efficacy of CCR8 antagonist alone or combined with pembrolizumab in GC.Results CCR8 was predominantly expressed on tumor-infiltrating Treg cells. High infiltration of intratumoral CCR8 + Treg cells predicted inferior clinical outcomes but superior immunotherapeutic responsiveness to pembrolizumab in GC. Transcriptomic and phenotypic analyses revealed that tumor-infiltrating CCR8+ Treg cells displayed an immunosuppressive phenotype that potentially attenuated the effective function of CD8+ T cells, leading to an immunosuppressive tumor microenvironment (TME). CCR8 antagonist dampened immunosuppressive function of tumor-infiltrating Treg cells and enhanced the efficacy of pembrolizumab-based immunotherapy in GC.Conclusions Tumor-infiltrating CCR8 + Treg cells display immunosuppressive phenotype and show both prognostic and predictive significance in GC. CCR8 antagonist dampens immunosuppressive function of tumor-infiltrating Treg cells and enhances the efficacy of pembrolizumab-based immunotherapy in GC. Combination of CCR8 antagonist and PD-1 blockade has a synergistic effect, and emerges as a potential personalized immunotherapeutic strategy for the patients with GC.Ethics Approval This study was approved by the Ethics Committee of Zhongshan Hospital, Fudan University (No. B2024-261).Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.