Intratumoral γδ T-Cell Infiltrates, Chemokine (C-C Motif) Ligand 4/Chemokine (C-C Motif) Ligand 5 Protein Expression and Survival in Patients With Hepatocellular Carcinoma

Background and Aims Hepatocellular carcinoma (HCC) is an aggressive malignancy which is often associated with a complex tumor microenvironment attributable to etiology-induced cellular inflammation. gamma delta T cells are known to detect and react to chronic inflammation, which is linked to cancer development, progression, and metastasis. Our recent genomic study revealed an increased infiltration of several immune cell types, including gamma delta T cells, in tumor microenvironments of a Thai HCC subtype associated with a good prognosis. Approach and Results Here, we quantified the amount of gamma delta T cells using a gamma delta T-cell-specific gene signature in 247 Chinese HCC patients. We also validated the gamma delta T-cell signature in American HCC patients. Additionally, such an association was only found in tumor transcriptomic data, but not in adjacent nontumor transcriptomic data, suggesting a selective enrichment of gamma delta T cells in the tumor microenvironment. Moreover, the gamma delta T-cell signature was positively correlated with the expression of natural killer cell receptor genes, such as NKG2D and cytolytic T-cell genes granzymes and perforin, suggesting a stronger T-cell-mediated cytotoxic activity. Furthermore, we found that the gamma delta T-cell-specific gene expression is positively correlated with the expression of chemokine (C-C motif) ligand 4 (CCL4)/chemokine (C-C motif) ligand 5 (CCL5) and C-C chemokine receptor type 1 (CCR1)/C-C chemokine receptor type 5 (CCR5), the receptors for gamma delta T cells. We validated these results using immunohistochemical analysis of formalin-fixed, paraffin-embedded tumor biopsies from 182 HCC patients. Moreover, we found evidence of CCL4/CCL5-mediated recruitment of gamma delta T cells both in vitro and in a murine orthotopic Hepa1-6 HCC model. Conclusions We propose that CCL4/CCL5 may interact with their receptor, CCR1/CCR5, which may facilitate the recruitment of gamma delta T cells from peripheral blood or peritumor regions to the tumor regions. Consequently, an increasing infiltration of gamma delta T cells in tumors may enhance antitumor immunity and improve patients' prognosis.

Automated summary

The study found an increased infiltration of gamma delta T cells in the tumor microenvironment of HCC patients, positively correlated with the expression of immune-related genes. Interaction between CCL4/CCL5 and their receptors CCR1/CCR5 may facilitate the recruitment of gamma delta T cells from peripheral blood or surrounding areas to tumor regions.