Abstract 901: KLF4-induced melanocyte-schwann plasticity promotes immune escape in melanoma via LAG3 checkpoint

Abstract Precision therapy is crucial to the successful treatment of rare tumors with limited treatment options. Here, we report a rare case of primary anterior mediastinal melanoma with liver metastasis. The patient had previously failed anti-PD1 treatment, leading us to profile the molecular features of the tumor to identify alternative therapeutic targets. Through comprehensive multi-omics analyses, we discovered a high degree of tumor cell plasticity in this rare case, with a subset of tumor cells displaying a Schwann cell phenotype evolved from melanocyte tumor cells. Cell-cell communication analysis revealed that the Schwann-like tumor cells may evade immune surveillance through the LAG3-LGALS3 immune checkpoint. The patient was then recommended for enrollment in a trial using combination therapy with anti-PD1 and anti-LAG3, and the disease remained stable for up to 24 months. Further investigation into the underlying mechanism showed that transcription factor KLF4-mediated transcription reprogramming drives B16 melanoma cell trans-differentiation into a Schwann cell phenotype. This trans-differentiation sensitizes the tumor cells to anti-LAG3 therapy. By analyzing melanoma tissue microarrays and external single-cell sequencing data, we found that this melanocyte-Schwann plasticity (MSP) existed in around 20% of melanoma cases. Moreover, a public immunotherapy cohort and our data indicate that MSP is associated with poor response to anti-PD1 treatment, suggesting that MSP may serve as a predictive biomarker for immunotherapy efficacy. Overall, our study not only provides a paradigm for precision immunotherapy in the context of rare tumors, but also reveals a potentially effective immunotherapeutic strategy for advanced melanoma with melanocyte-Schwann plasticity. Citation Format: An Zhao, Xuefei Liu, Zhixiang Zuo. KLF4-induced melanocyte-schwann plasticity promotes immune escape in melanoma via LAG3 checkpoint [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 901.