Endogenous CCL21-Ser deficiency reduces B16-F10 melanoma growth by enhanced antitumor immunity

Ryonosuke Fujie; Kaoru Kurowarabe; Yuki Yamada; Kakeru Fujiwara; Hayato Nakatani; Kenta Tsutsumi; Ryota Hayashi; Hinami Kawahata; Megumi Miyamoto; Madoka Ozawa; Tomoya Katakai; Yousuke Takahama; Izumi Ohigashi; Haruko Hayasaka

doi:10.1016/j.heliyon.2023.e19215

Endogenous CCL21-Ser deficiency reduces B16-F10 melanoma growth by enhanced antitumor immunity

Heliyon. 2023 Aug 19;9(8):e19215. doi: 10.1016/j.heliyon.2023.e19215. eCollection 2023 Aug.

Authors

Ryonosuke Fujie¹, Kaoru Kurowarabe¹, Yuki Yamada², Kakeru Fujiwara¹, Hayato Nakatani², Kenta Tsutsumi², Ryota Hayashi¹, Hinami Kawahata², Megumi Miyamoto¹, Madoka Ozawa³, Tomoya Katakai³, Yousuke Takahama^{4

5}, Izumi Ohigashi⁴, Haruko Hayasaka^{1

2

6}

Affiliations

¹ Department of Science, Graduate School of Science and Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502, Japan.
² Faculty of Science & Engineering, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502, Japan.
³ Department of Immunology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan.
⁴ Division of Experimental Immunology, Institute of Advanced Medical Sciences, University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
⁵ Thymus Biology Section, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
⁶ Research Institute for Science and Technology, Kindai University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502, Japan.

Abstract

The chemokine CCL21 regulates immune and cancer cell migration through its receptor CCR7. The Ccl21a gene encodes the isoform CCL21-Ser, predominantly expressed in the thymic medulla and the secondary lymphoid tissues. This study examined the roles of CCL21-Ser in the antitumor immune response in Ccl21a-knockout (KO) mice. The Ccl21a-KO mice showed significantly decreased growth of B16-F10 and YUMM1.7 melanomas and increased growth of MC38 colon cancer, despite no significant difference in LLC lung cancer and EO771 breast cancer. The B16-F10 tumor in Ccl21a-KO mice showed melanoma-specific activated CD8⁺ T cell and NK cell infiltration and higher Treg counts than wild-type mice. B16-F10 tumors in Ccl21a-KO mice showed a reduction in the positive correlation between the ratio of regulatory T cells (Tregs) to activated CD8⁺ T cells and tumor weight. In Ccl21a-KO tumor, the intratumoral Tregs showed lower co-inhibitory receptors TIM-3 and TIGIT. Taken together, these results suggest that endogenous CCL21-Ser supports melanoma growth in vivo by maintaining Treg function and suppressing antitumor immunity by CD8⁺ T cells.

Keywords: CD8; Chemokine; Lymph node; Melanoma; Treg.