CCL21‐Ser expression in melanoma cells recruits CCR7+ naïve T cells to tumor tissues and promotes tumor growth

• Published in: Cancer science 2023-09, Vol.114 (9), p.3509-3522
• Main Authors: Miyamoto, Megumi, Kawato, Yuki, Fujie, Ryonosuke, Kurowarabe, Kaoru, Fujiwara, Kakeru, Nobusawa, Reika, Hayashi, Ryota, Iida, Kei, Ohigashi, Izumi, Hayasaka, Haruko
• Format: Article
• Language: English
• Subjects: Adoptive transfer; Albinism; Antibodies; Breast cancer; CC chemokine receptors; CCL21; CCR7; Cell culture; Cell migration; Cell proliferation; Cell survival; chemokine; Chemokines; Dendritic cells; Epithelial cells; Flow cytometry; L-selectin; Laboratory animals; Life sciences; Lymphatic system; Lymphocytes; Lymphocytes T; Melanoma; Metastases; Metastasis; naïve T cell; Original; ORIGINAL ARTICLES; Penicillin; Skin cancer; Stromal cells; Thymus; Thymus gland; Transgenic animals; Tumor microenvironment; Tumors
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15902

CCL21‐Ser, a chemokine encoded by the Ccl21a gene, is constitutively expressed in the thymic epithelial cells and stromal cells of secondary lymphoid organs. It regulates immune cell migration and survival through its receptor CCR7. Herein, using CCL21‐Ser‐expressing melanoma cells and the Ccl21a‐deficient mice, we demonstrated the functional role of cancer cell‐derived CCL21‐Ser in melanoma growth in vivo. The B16‐F10 tumor growth was significantly decreased in Ccl21a‐deficient mice compared with that in wild‐type mice, indicating that host‐derived CCL21‐Ser contributes to melanoma proliferation in vivo. In Ccl21a‐deficient mice, tumor growth of melanoma cells expressing CCL21‐Ser was significantly enhanced, suggesting that CCL21‐Ser from melanoma cells promotes tumor growth in the absence of host‐derived CCL21‐Ser. The increase in tumor growth was associated with an increase in the CCR7+ CD62L+ T cell frequency in the tumor tissue but was inversely correlated with Treg frequency, suggesting that naïve T cells primarily promote tumor growth. Adoptive transfer experiments demonstrated that naïve T cells are preferentially recruited from the blood into tumors with melanoma cell‐derived CCL21‐Ser expression. These results suggest that CCL21‐Ser from melanoma cells promotes the infiltration of CCR7+ naïve T cells into the tumor tissues and creates a tumor microenvironment favorable for melanoma growth. The CCL21‐Ser is a homeostatic chemokine that is crucial for immune cell migration and tissue localization. By using Ccl21a‐knockout mice and CCL21‐Ser expressing melanoma cells, we clearly demonstrated that melanoma‐derived CCL21‐Ser increased CCR7+ naïve T cell infiltration into tumors and contributed to tumor growth in vivo. Our study suggests that CCL21‐Ser in melanoma creates a tumor microenvironment favorable for melanoma growth.