ST8Sia6 expression on tumors inhibits the immune response

Project: Research project

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Abstract ? Supplement Checkpoint blockade, which targets inhibitory receptors that suppress successful T cell responses to tumors, demonstrates the critical role that the immune response plays against cancer. However, not all cancers respond to immunotherapy or checkpoint blockade targeting PD-1 or CTLA-4 on T cells. Thus, many tumors may target other inhibitory receptors or different components of the immune system to block it from mounting an effective response. One family of inhibitory receptors on immune cells is the Siglec family, which recognize ligands with sialic acid modifications on cell surface glycoproteins and glycolipids. There are twenty eukaryotic sialic acid transferases, each with different specificity for preferred linkages, targets, and number of sialic acids added. It has been long recognized that tumors alter the type and frequency of glycosylation and sialic acid addition on the cell surface. In particular, increased incorporation of sialic acid is frequently observed in cancer, although the function of hyper-sialylation in promoting and sustaining tumor growth is not well understood. Interestingly, using the COSMIC database, we found that while 389 human tumors over- expressed the sialic acid transferase ST8Sia6, none under-expressed ST8Sia6; this indicates a strong selective advantage for tumors with high ST8Sia6 expression, although the function of ST8Sia6 in cancer is not known. We demonstrated that ST8Sia6 overexpression in either MC38 or B16-F10 tumor cell lines accelerated tumor growth in mice. We also showed that ST8Sia6 generates ligands for the inhibitory Siglec, Siglec-E, whose expression is restricted to innate immune cells. The growth advantage of ST8Sia6-expressing tumor cells was lost upon injection into Siglec-E knockout mice, demonstrating that the primary effect of ST8Sia6 overexpression is on inhibition of the immune response of the host rather than an intrinsic effect on cell growth. Overexpression of ST8Sia6 in a spontaneous model of colon cancer dramatically decreased survival to 2-3 months instead of 6 months, demonstrating the strong effect of ST8Sia6 overexpression on tumor cell growth in vivo. The focus of this supplement is to use tools generated by Drs. Carolyn Bertozzi and Sharon Pitteri under the NIH Common Fund Glycoscience Program (CF-GSP) to 1) identify the glycans which are modified by ST8Sia6 in cancer cells, macrophages, and dendritic cells and 2) identify the proteins whose glycans are modified by ST8Sia6 in cancer cells, macrophages, and dendritic cells which associate with Siglec-E. There is no overlap between the experiments proposed here to identify the targets of ST8Sia6 and the currently funded R01, but this supplement extends the work to identify the critical glycans/proteins modified by ST8Sia6 which inhibit the immune response to tumors.
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