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

Abstract

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. γδ 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 γδ T cells, in tumor microenvironments of a Thai HCC subtype associated with a good prognosis. Approach and Results Here, we quantified the amount of γδ T cells using a γδ T‐cell‐specific gene signature in 247 Chinese HCC patients. We also validated the γδ 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 γδ T cells in the tumor microenvironment. Moreover, the γδ 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 γδ 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 γδ 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 γδ 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 γδ T cells from peripheral blood or peritumor regions to the tumor regions. Consequently, an increasing infiltration of γδ T cells in tumors may enhance antitumor immunity and improve patients’ prognosis.

CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands

“…In a tumor, an active immune response results in the production of CCL3 and CCL4 by B cells [ 116 ] and basophils [ 117 ]. The produced chemokines act as chemoattractants for anti-cancer TIL with CCR1 and CCR5 [ 115 , 118 , 119 , 120 , 121 ]. However, in a tumor both CCL3 and CCL4 may be cleaved by cathepsin D [ 122 ] and chemokine decoy receptor ACKR2/D6 [ 2 , 123 ], which suppresses the anti-cancer effect of these two CC chemokines.…”

Innate lymphocytes: pathogenesis and therapeutic targets of liver diseases and cancer

“…Infiltrating γδ T cells showed stronger cytotoxic activity with higher expression of NKG2D, granzymes, and perforin, indicating that γδ T cells may exhibit antitumor activities in the progression of HCC. 192 However, chemotherapy accelerated immune-senescence and functional impairment of the tumorinfiltrating Vδ2 + T cell subset from liver metastases in patients with CRC, observed as a relative increase in terminally differentiated CD27 neg /CD45RA pos (TEMRA) cells and increased expression of the senescence marker CD57, coupled with impairments in cytotoxicity and production of TNF-α and IFN-γ. 193 Additionally, significantly lower expression of IL-2 and IL-21 in γδ T cells was observed in HCC patients compared with healthy control volunteers, accounting for their reduced cytotoxic capacity.…”

SLC1A4: A Powerful Prognostic Marker and Promising Therapeutic Target for HCC

“…SLC1A4 expression was also significantly associated with immune subtype, stroma score and tumor stem cell RNAs score. It is well-accepted that chemokines play key role in recruiting and positioning of immune cells in the tumor microenvironment (26)(27)(28)(29). For example, CCL15 and IL12A were reported to play an important role on recruited CCR1+ CD14+ monocytes and natural killer (NK) cell in HCC respectively (30,31).…”