Proinflammatory macrophages release CXCL5 to regulate T cell function and limit effects of αPD-1 in steatosis-driven liver cancer
Background & Aims: Steatosis is a comorbid factor for cancer development. Patients with steatosis do not respond well to current immune checkpoint therapy (CPI) treatment. We explored the roles of neutrophil-activating chemokines (NACs) in the response of steatosis/liver cancer to CPI. Metho...
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Elsevier
2025-06-01
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| author | Taojian Tu Handan Hong Diala Alhousari Lina He Mario Alba Yiwei Gu Brittney Hua Phillip Nguyen Qi Tang Tianyi Xia Karam Ashouri Anastasia Martynova Christina Nakhoul Whitaker Cohn Genshu Wang Geyang Xu Zhang-Xu Liu Curtis Okamoto Enrique Cadenas Julian Whitelegge Weiming Yuan Shefali Chopra Keigo Machida Liyun Yuan Anthony El-Khoueiry Bangyan L. Stiles |
| author_facet | Taojian Tu Handan Hong Diala Alhousari Lina He Mario Alba Yiwei Gu Brittney Hua Phillip Nguyen Qi Tang Tianyi Xia Karam Ashouri Anastasia Martynova Christina Nakhoul Whitaker Cohn Genshu Wang Geyang Xu Zhang-Xu Liu Curtis Okamoto Enrique Cadenas Julian Whitelegge Weiming Yuan Shefali Chopra Keigo Machida Liyun Yuan Anthony El-Khoueiry Bangyan L. Stiles |
| author_sort | Taojian Tu |
| collection | DOAJ |
| description | Background & Aims: Steatosis is a comorbid factor for cancer development. Patients with steatosis do not respond well to current immune checkpoint therapy (CPI) treatment. We explored the roles of neutrophil-activating chemokines (NACs) in the response of steatosis/liver cancer to CPI. Methods: We used a steatosis-driven liver cancer model induced by the deletion of Pten in the liver (LiPten) and a high-fat diet + carbon tetrachloride (CCl4) fibrosis model to study the effects of targeting CXCL5. We also studied the role of CXCL5 in the liver immune microenvironment in vitro and in vivo. ANOVA/t tests were used for data analysis. Results: Using LiPten steatosis-tumor mice, we identified CXCL5 as the NAC most robustly upregulated as steatosis progresses to cancer (>100 fold, n = 6–11). We also validated this observation in patient samples. When used together with αPD-1, inhibiting the NAC receptor CXCR2 promoted (100% vs. 80% in untreated LiPten mice), whereas anti-CXCL5 suppressed (25%), tumor progression (n = 4–6) suggesting unique functions of CXCL5 independent of CXCR2. Similar effects were observed for anti-CXCL5 (0/4 with fibrosis) vs. CXCR2 inhibition (4/4 with fibrosis) of fibrosis in the HFD + CCl4 model. Using a Transwell assay, we identified a novel inhibitory function of CXCL5 in the recruitment of CD4+ T cells (p <0.02, n = 4) and potentiation of CD8+ T cell cytotoxicity (p <0.001, n = 4). In vivo, we showed that neutralizing CXCL5 increased the CD8/CD4 ratio (p = 0.03 and 0.07) and synergized with αPD-1 for its anti-tumor and anti-fibrosis activity (n = 4–6). Conclusions: Our discovery of the novel inhibitory role of CXCL5 in T cells suggests that NACs have additional functions in modulating the immune system beyond neutrophil chemotaxis. The discovery of this novel CXCL5 role presents additional therapeutical targets alongside current immune checkpoint therapy. Impact and implications: In this study, we investigated the role of CXCL5 in the progression from steatosis to liver cancer. We uncovered a novel inhibitory role of CXCL5 in T cell recruitment, with implications for NAC-targeted therapy and immune checkpoint synergy in liver cancer. We believe our findings will be of interest to physicians, researchers, and patients interested in therapeutic development and translational research in liver disease. |
| format | Article |
| id | doaj-art-9348c02f5bb2468abdc42b45af7024bb |
| institution | DOAJ |
| issn | 2589-5559 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
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| series | JHEP Reports |
| spelling | doaj-art-9348c02f5bb2468abdc42b45af7024bb2025-08-20T03:10:30ZengElsevierJHEP Reports2589-55592025-06-017610138510.1016/j.jhepr.2025.101385Proinflammatory macrophages release CXCL5 to regulate T cell function and limit effects of αPD-1 in steatosis-driven liver cancerTaojian Tu0Handan Hong1Diala Alhousari2Lina He3Mario Alba4Yiwei Gu5Brittney Hua6Phillip Nguyen7Qi Tang8Tianyi Xia9Karam Ashouri10Anastasia Martynova11Christina Nakhoul12Whitaker Cohn13Genshu Wang14Geyang Xu15Zhang-Xu Liu16Curtis Okamoto17Enrique Cadenas18Julian Whitelegge19Weiming Yuan20Shefali Chopra21Keigo Machida22Liyun Yuan23Anthony El-Khoueiry24Bangyan L. Stiles25Pharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USAPharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USAPharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USAPharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USAPharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USAPharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USAPharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USAPharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USAPharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USAPharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USADivision of Medical Oncology, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, 1975 Zonal Ave., Los Angeles, CA 90033, USADivision of Medical Oncology, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, 1975 Zonal Ave., Los Angeles, CA 90033, USADivision of Medical Oncology, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, 1975 Zonal Ave., Los Angeles, CA 90033, USADepartment of Psychiatry and Biobehavioral Sciences, UCLA David Geffen School of Medicine, 760 Westwood Plaza, Los Angeles, CA 90024, USADepartment of Hepatic Surgery and Liver Transplantation Center, Third Affiliated Hospital of Sun Ye-Sen University, No. 600 Tianhe Road, Guangdong, 518060, ChinaDepartment of Physiology, School of Medicine, Jinan University, 601 Huangpu Blvd W, Tianhe District, Guangdong, 518060, ChinaPharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USAPharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USAPharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USADepartment of Psychiatry and Biobehavioral Sciences, UCLA David Geffen School of Medicine, 760 Westwood Plaza, Los Angeles, CA 90024, USADepartment of Molecular Microbiology and Immunology, Keck School of Medicine, 2011 Zonal Ave., University of Southern California, Los Angeles, CA 90033, USADepartment of Medicine, Keck School of Medicine, University of Southern California, 1975 Zonal Ave., Los Angeles, CA 90033, USADepartment of Molecular Microbiology and Immunology, Keck School of Medicine, 2011 Zonal Ave., University of Southern California, Los Angeles, CA 90033, USADepartment of Medicine, Keck School of Medicine, University of Southern California, 1975 Zonal Ave., Los Angeles, CA 90033, USADivision of Medical Oncology, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, 1975 Zonal Ave., Los Angeles, CA 90033, USAPharmacology and Pharmaceutical Sciences, Mann School of Pharmacy, University of Southern California, 1985 Zonal Ave., Los Angeles, CA 90033, USA; Department of Pathology, Keck School of Medicine, University of Southern California, 1975 Zonal Ave., Los Angeles, CA 90033, USA; Corresponding author. Address: Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA. Tel.: +1 323 442 2184; fax: +1 323 224 7473.Background & Aims: Steatosis is a comorbid factor for cancer development. Patients with steatosis do not respond well to current immune checkpoint therapy (CPI) treatment. We explored the roles of neutrophil-activating chemokines (NACs) in the response of steatosis/liver cancer to CPI. Methods: We used a steatosis-driven liver cancer model induced by the deletion of Pten in the liver (LiPten) and a high-fat diet + carbon tetrachloride (CCl4) fibrosis model to study the effects of targeting CXCL5. We also studied the role of CXCL5 in the liver immune microenvironment in vitro and in vivo. ANOVA/t tests were used for data analysis. Results: Using LiPten steatosis-tumor mice, we identified CXCL5 as the NAC most robustly upregulated as steatosis progresses to cancer (>100 fold, n = 6–11). We also validated this observation in patient samples. When used together with αPD-1, inhibiting the NAC receptor CXCR2 promoted (100% vs. 80% in untreated LiPten mice), whereas anti-CXCL5 suppressed (25%), tumor progression (n = 4–6) suggesting unique functions of CXCL5 independent of CXCR2. Similar effects were observed for anti-CXCL5 (0/4 with fibrosis) vs. CXCR2 inhibition (4/4 with fibrosis) of fibrosis in the HFD + CCl4 model. Using a Transwell assay, we identified a novel inhibitory function of CXCL5 in the recruitment of CD4+ T cells (p <0.02, n = 4) and potentiation of CD8+ T cell cytotoxicity (p <0.001, n = 4). In vivo, we showed that neutralizing CXCL5 increased the CD8/CD4 ratio (p = 0.03 and 0.07) and synergized with αPD-1 for its anti-tumor and anti-fibrosis activity (n = 4–6). Conclusions: Our discovery of the novel inhibitory role of CXCL5 in T cells suggests that NACs have additional functions in modulating the immune system beyond neutrophil chemotaxis. The discovery of this novel CXCL5 role presents additional therapeutical targets alongside current immune checkpoint therapy. Impact and implications: In this study, we investigated the role of CXCL5 in the progression from steatosis to liver cancer. We uncovered a novel inhibitory role of CXCL5 in T cell recruitment, with implications for NAC-targeted therapy and immune checkpoint synergy in liver cancer. We believe our findings will be of interest to physicians, researchers, and patients interested in therapeutic development and translational research in liver disease.http://www.sciencedirect.com/science/article/pii/S258955592500062XFibrosisHCCNAFLD/NASHPTEN |
| spellingShingle | Taojian Tu Handan Hong Diala Alhousari Lina He Mario Alba Yiwei Gu Brittney Hua Phillip Nguyen Qi Tang Tianyi Xia Karam Ashouri Anastasia Martynova Christina Nakhoul Whitaker Cohn Genshu Wang Geyang Xu Zhang-Xu Liu Curtis Okamoto Enrique Cadenas Julian Whitelegge Weiming Yuan Shefali Chopra Keigo Machida Liyun Yuan Anthony El-Khoueiry Bangyan L. Stiles Proinflammatory macrophages release CXCL5 to regulate T cell function and limit effects of αPD-1 in steatosis-driven liver cancer JHEP Reports Fibrosis HCC NAFLD/NASH PTEN |
| title | Proinflammatory macrophages release CXCL5 to regulate T cell function and limit effects of αPD-1 in steatosis-driven liver cancer |
| title_full | Proinflammatory macrophages release CXCL5 to regulate T cell function and limit effects of αPD-1 in steatosis-driven liver cancer |
| title_fullStr | Proinflammatory macrophages release CXCL5 to regulate T cell function and limit effects of αPD-1 in steatosis-driven liver cancer |
| title_full_unstemmed | Proinflammatory macrophages release CXCL5 to regulate T cell function and limit effects of αPD-1 in steatosis-driven liver cancer |
| title_short | Proinflammatory macrophages release CXCL5 to regulate T cell function and limit effects of αPD-1 in steatosis-driven liver cancer |
| title_sort | proinflammatory macrophages release cxcl5 to regulate t cell function and limit effects of αpd 1 in steatosis driven liver cancer |
| topic | Fibrosis HCC NAFLD/NASH PTEN |
| url | http://www.sciencedirect.com/science/article/pii/S258955592500062X |
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