Na Zhao1,2, Hien Dang1, Lichun Ma1, Sean P Martin1, Marshonna Forgues1, Kris Ylaya3, Stephen M Hewitt3, Xin Wei Wang1,4. 1. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD. 2. Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China. 3. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD. 4. Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
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.
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.
Authors: Jittiporn Chaisaingmongkol; Anuradha Budhu; Hien Dang; Siritida Rabibhadana; Benjarath Pupacdi; So Mee Kwon; Marshonna Forgues; Yotsawat Pomyen; Vajarabhongsa Bhudhisawasdi; Nirush Lertprasertsuke; Anon Chotirosniramit; Chawalit Pairojkul; Chirayu U Auewarakul; Thaniya Sricharunrat; Kannika Phornphutkul; Suleeporn Sangrajrang; Maggie Cam; Ping He; Stephen M Hewitt; Kris Ylaya; Xiaolin Wu; Jesper B Andersen; Snorri S Thorgeirsson; Joshua J Waterfall; Yuelin J Zhu; Jennifer Walling; Holly S Stevenson; Daniel Edelman; Paul S Meltzer; Christopher A Loffredo; Natsuko Hama; Tatsuhiro Shibata; Robert H Wiltrout; Curtis C Harris; Chulabhorn Mahidol; Mathuros Ruchirawat; Xin W Wang Journal: Cancer Cell Date: 2017-06-22 Impact factor: 31.743
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