CCL5 production by fibroblasts through a local renin–angiotensin system in malignant melanoma affects tumor immune responses

• Published in: Journal of cancer research and clinical oncology 2021-07, Vol.147 (7), p.1993-2001
• Main Authors: Nakamura, Kenta, Kiniwa, Yukiko, Okuyama, Ryuhei
• Format: Article
• Language: English
• Subjects: Angiotensin; Angiotensin receptors; Antibodies; Antigens; Antitumor activity; Apoptosis; Blood levels; Cancer Research; Chemokines; Fibroblasts; Growth inhibition; Hematology; Immunoregulation; Immunosuppression; Internal Medicine; Lymphocytes T; Macrophages; Medicine; Medicine & Public Health; Melanoma; Oncology; Original Article – Cancer Research; PD-1 protein; Renin; Skin cancer; Tumor microenvironment
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-021-03612-8

Purpose To enhance the antitumor effects of anti-programmed death-1 (PD-1) antibodies, it is important to reverse cancer-induced immunosuppression. We previously reported that a localized renin–angiotensin system in the tumor microenvironment inhibited tumor immunity via macrophages. In this study, we analyzed the underlying mechanism through which fibroblasts express tumor immunity influenced by the angiotensin receptor. Methods We used an angiotensin receptor inhibitor (ARB) to inhibit renin–angiotensin system. Furthermore, angiotensin receptors were knocked out from mice fibroblasts, which were then collected. The fibroblasts and a malignant melanoma were then transfused into a mouse model and tumor immunity response was analyzed. Results Fibroblasts produced CC motif chemokine ligand 5 (CCL5) on renin–angiotensin system stimulation, and this production decreased after ARB administration. In mice with transplanted malignant melanoma, ARB administration resulted in decreased CCL5 concentration in the blood, increase in tumor-infiltrating T cells, decrease in regulatory T cells, as well as an increase in tumor antigen-specific T-cell responses. The mice in which the angiotensin receptor knockout fibroblasts and malignant melanoma were transplanted showed a similar decrease in CCL5 concentration and increased tumor antigen-specific T-cell responses. Furthermore, ARB and anti-PD-1 antibody were administered in combination, which resulted in significantly better tumor growth inhibition over monotherapy. Conclusion Inhibiting renin–angiotensin system restored the therapeutic efficacy of inhibited anti-PD-1 antibodies. Thus, this could be considered a valid approach to enhance the therapeutic efficacy of anti-PD-1 antibodies.