Shapiro, Michael

Abstract T-cell targeted immunotherapy has resulted in novel treatments for multiple cancers and has been the primary focus in cancer immunotherapy. However, many patients still fail checkpoint therapies due to immune suppression mechanisms driven by cells, such as tolerogenic M2-like macrophages, which support tumor growth. ST8Sia6, a sialyltransferase, generates α2,8-linked disialic acids on O-linked glycoproteins. Cancer patients with high ST8Sia6 expression exhibit reduced survival as compared to patients with low expression, but the mechanism is unknown. We generated MC38 and B16–F10 murine cancer cell lines that overexpress ST8Sia6. Expression of ST8Sia6 accelerated flank tumor growth in both single and dual flank injection models as compared to parental tumors. In vivo, macrophage polarization was altered in ST8Sia6 expressing tumors. At day 7, tumor associated macrophages (TAMs) from ST8Sia6 negative MC38 tumors were primarily M1-like, while TAMs from ST8Sia6 expressing MC38 tumors were predominately M2-like. Tumor growth and M2-like polarization was dependent Siglec-E. Siglec-E present on innate cells bind α2,8-linked disialic acids generated by ST8Sia6 and suppress immune activation. Therefore, ST8Sia6 overexpressing tumors engage Siglec-E, suppressing the immune response and increasing tumor growth. ST8Sia6 overexpression in a spontaneous murine colon cancer model decreased survival from over 6 months to 2–3 months. Therefore, ST8Sia6 expression in tumors may promote tumor growth by promoting tolerogenic immune responses.