Abstract A041: Combined inhibition of S100A4 and TIGIT suppresses late-stage breast cancer metastasis to the lung by activating T and NK cells

Abstract Cancer metastasis is responsible for approximately 90% of cancer-related deaths but a very few treatment options exist currently. For decades, the role of S100A4 in promoting metastasis has been validated in multiple ways. More recently, our single cell RNA-sequencing analysis of human gliomas and other cancers showed that S100A4 is highly expressed in immune suppressive myeloid and T cells. Consistently, removing S100A4 from the host microenvironment suppresses tumor growth from injected MC38, BL16, or E0771 murine cancer cells, strongly supporting its pro-tumorigenic role in the TME and nominating it as a novel immunotherapy target. To translate these findings, we developed a novel antibody against the human S100A4 protein to block its function in the TME. The monoclonal antibody (mAb) S1004-11 effectively suppresses breast cancer metastasis in two different mouse models. Mechanistically, S1004-11 mAb treatment blocks the pre-metastatic niche formation in the lung by suppressing neutrophil infiltration, activating NK and T cells, and altering cell-to-cell communication among stromal and immune cells. Additionally, S100A4-11 treatment reduces circulating M-MDSCs and Tregs in the blood, and CD163+ but not CD206+ macrophages in the primary breast tumor. Notably, single cell RNA-seq and cell:cell communication analyses suggest that NK cells in the lung are suppressed by TIGIT signaling, suggesting that anti-TIGIT treatment may suppress lung metastases and synergize with S100A4 inhibition. To simulate clinical scenario where many breast cancer patients are diagnosed with existing micro or macro metastases, we tested whether S100A4-11 or anti-TIGIT antibody can suppress lung metastases when the treatment is initiated after the lung niche formation is complete. While S100A4-11 or anti-TIGIT treatment alone was not sufficient to suppress lung metastases at this late stage, the combined treatment of S100A4-11 and TIGIT significantly reduced lung nodule formation. Taken together, these results indicate that S100A4 can suppress breast cancer metastasis through different mechanisms at different stages of metastases progression, and nominates anti-S100A4+anti-TIGIT as a novel combination therapy to block late lung metastasis. Citation Format: Jia-Shiun Leu, Hui Deng, Wei Xiong, Han Nhat Tran, Chihiro Hashimoto, Fransisca Leonard, Thomas Wong, Nourhan Abdelfattah, Zhiqiang An, Ningyan Zhang, Kyuson Yun. {Abstract title} [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A041.