Immunomodulatory agents blocking the immune checkpoint PD-1/PD-L1 (PD) pathway have shown remarkable
clinical benefits and constitute a new standard of care for cancer treatment. The success of these agents is due
to the prominent immunosuppressive function of the PD-1 receptor alongside the selective expression of its
ligand, PD-L1, in the tumor microenvironment (TME), leading to a favorable efficacy-to-toxicity ratio. However,
despite the vast advances provided by anti-PD therapy, only a subset of patients develops a long-term response,
illustrating the need for identifying new immune modulators in the TME, especially in PD-L1 negative tumors. To
achieve this, we built the first genome-scale T-cell activity screen of human membrane proteins and identified
Siglec-15 as a critical immune suppressor with broad upregulation on various cancer types and a new target for
cancer immunotherapy. Siglec-15 has unique molecular features compared with many other known checkpoint
inhibitory ligands. It shows dominant expression on cancer cells, besides tumor-associated macrophages, and
exhibits PD-L1 mutually exclusive expression pattern in human cancers. Siglec-15 blockade by a monoclonal
antibody shows therapeutic efficacy in mouse tumor models and human cancer cell culture systems and results
in amplified T cell responses. Siglec-15 may represent a novel class of immune checkpoint ligands with tumor-
associated expression and divergent mechanisms of action to PD-L1, with important implications for anti-PD
unresponsive patients. Based on these results, we have developed an anti-human Siglec-15 antibody (NC318)
with the related phase I/II clinical trials currently ongoing for PD-1 refractory metastatic solid cancers. Although
the preliminary clinical trial results are quite promising, the clear elucidation of the immune suppressive
mechanism of Siglec-15 in the tumor-microenvironment will advance the clinical translation of this novel program.
Other than modulating T cell function, our new findings also suggest that Siglec-15 represents a potential novel
axis of control for myeloid cells, a key immune cell subset critical in shaping the tumor microenvironment which
have a relative lack of successful clinical targets. Beyond this, important questions remain to optimize Siglec-15-
related therapy, such as its receptor(s), induction mechanisms, and potential additive effects or synergies with
existing treatments. In this project, through two complementary aims, we will leverage our expertise in cancer
immunology and immunotherapy to: 1) determine the potential immune function of Siglec-15 beyond T cells,
particularly on myeloid cells, and to characterize functional Siglec-15 receptors on both myeloid cells and T cells;
2) examine the role of oncogenic KRAS mutants as induction mechanism of Siglec-15 expression on cancer
cells and identify better anti-Siglec-15 combinatorial therapies using two oncogenic KRAS mutant-associated
syngeneic orthotopic mouse models of pancreatic and ovarian cancer. Collectively, our proposed studies will
facilitate our understanding of a novel PD-L1 mutually exclusive immune checkpoint and enhance Siglec-15-
based therapeutic approaches for anti-PD-1/PD-L1 insensitive cancers.