Abstract 2632: IL10RB is a key molecule that regulates tumor escape through invadopodium formation and immune dysfunction

Abstract Purpose: Many molecular mechanisms underlying tumor escape, in which cancer cells undergo EMT and thereby acquire metastatic potential and cancer stemness, have been elucidated, and these efforts have led to the development of various novel drugs. However, many patients do not necessarily benefit from the treatments. This may be because cancer cells diversify and evolve through intrinsic changes that occur within the cancer cells themselves via EMT, and extrinsic changes that are modified by the host environment, in an attempt to escape the attacks of therapeutics and immune surveillance. Considering this situation, further in-depth research is needed to achieve complete cure in more patients. In this study, we focused on the changes in gene expression that occur in cancer cells after achieving EMT, and attempted to elucidate the evolutionary mechanisms that further promote tumor escape leading to robust treatment resistance. Results: We comprehensively analyzed gene expression in mouse melanoma B16-F10 cells stably expressing Snail, a key EMT-governing transcription factor, by GeneChip microarray, and found that IL10RB expression was strikingly increased as compared to that of mock control. Transfection with siRNA-snail into the cells abrogated both Snail and IL10RB expression, suggesting that this is regulated by Snail. Transfection with siRNA-il10rb significantly reduced cell invasion, adhesion, and chemoresistance as compared to transfection with control siRNA, suggesting a key functional role of IL10RB in tumor malignancy. Il10rb gene transduction into mouse IL10RB(low) cell lines (NHOS and Colon26) significantly enhanced cell invasion, adhesion, and chemoresistance, accompanied by dramatic morphological changes - formation of numerous tentacles/invadopodia. RNA-sequencing analysis of the IL10RB transfectants revealed that gene expression of actin and related genes, which are required for invadopodia formation and drug resistance, and of enzymes, which are required for invasion and metastasis, was markedly increased than that in mock control. In the in vivo settings, IL10RB+ tumor growth and metastasis were extremely slower after implantation in mice than those of mock control. However, T cells and NK cells were dramatically decreased in the spleens of the IL10RB+ tumor-implanted mice, and their cytotoxic activity was also significantly reduced, suggesting induction of immune suppression and dysfunction. Surprisingly, chemotherapy significantly exacerbated both IL10RB+ tumor growth and metastasis in the mice, while immunotherapy with anti-IL10RB blocking mAb significantly induced anti-tumor effects without such adverse events. Conclusions: These results suggest that IL10RB is a key molecule that regulates tumor escape and intractability post Snail-induced EMT. Targeting IL10RB may be a promising strategy for improving clinical outcomes in cancer therapy. Citation Format: Chie Kudo-Saito, Hiroki Ozawa, Hiroshi Imazeki. IL10RB is a key molecule that regulates tumor escape through invadopodium formation and immune dysfunction [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 2632.