Mast Cell-Derived TSLP Triggers an Allergic Response, Thereby Suppressing the Early Stage of Melanoma Development

Background: An allergic reaction is a hypersensitive immune reaction. Patients with allergic disorders have a lower incidence of certain cancers. Nevertheless, the role and underlying detailed mechanisms of allergic reaction in cancer development remain obscure. We sought to investigate the role of mast cell-mediated allergic reaction in the early stage of melanoma development. Methods: B16F10 melanoma-bearing animal models and in vitro models were used to examine the function and precise mechanism of mast cell-mediated allergic reactions in the melanoma development. Finding: Here, we revealed that mast cell-mediated allergic reaction caused autophagy and apoptosis in melanoma by raising thymic stromal lymphopoietin (TSLP) levels, resulting in improved survival of tumor control mice. Targeted depletion of TSLP decreased survival in tumor control mice, whereas TSLP injection increased survival through boosting allergic responses. Single-cell RNA sequencing analysis revealed that TSLP decreased the number of melanocytes, increased the number of T cells, and raised the levels of mast cell-derived allergy-promoting factors compared to tumor control. Moreover, TSLP enhanced the immune response and allergic reactions in immunodeficient mice, resulting in the suppression of melanoma development. Coincidently, patients with melanoma had lower serum levels of TSLP than healthy individuals. Furthermore, invitro stimulation of melanocytes with mast cell-derived TSLP prompted apoptosis of melanoma by inducing the autophagy. Interpretation: Therefore, our findings suggest that mast cell-derived TSLP directly/indirectly suppressed the early stage of melanoma development by enhancing immunity through triggering allergic reactions. Funding: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2021R1A2C1005166). Declaration of Interest: The authors declare that they have no competing interests. Ethical Approval: Human study was approved by the Bioethics Committee of Kyung Hee University [KHSIRB-19-326(EA)]. All samples derived from the National Biobank of Korea were obtained with informed consent under institutional review board-approved protocols. All animal experimental procedures were conducted in accordance with current laws and guidelines for the care and use of laboratory animals approved by the Animal Ethics Committee of Kyung Hee University [KHUASP (SE)-17-157].