Cancer and autoimmune diseases are nowadays amongst the deadliest pathologies all over the world, becoming a serious concern for public health, as they keep producing millions of deaths annually. In this regard, T lymphocytes are key immune cells in the development of effective adaptive responses against these pathologies. Understanding how the activity and proliferation of these lymphocytes is regulated at cellular and molecular level is essential to develop effective therapies. Overall, the response delivered by T cells is determined by several membrane receptors that might trigger either stimulatory/co-stimulatory effects, leading to T cell proliferation, or instead, inhibitory effects that make T cells remain anergic and become tolerant to the inspected antigen. In particular, siglecs are membrane receptors that prime inhibitory effects on T cells upon engaging by sialic-acid containing antigens (self signature). This inhibitory behavior has been widely described to be exploited by hypersialylated tumoral cells to evade T cell responses. Over the last two decades, siglecs have progressively gained interest as therapeutic targets, given that their efficient blockage in tumors might help to restore T cell function. While some advancements have been achieved for few human siglecs like CD22 and CD33 so far, others remain pretty unknown, especially from a molecular point of view. Siglec-15 is a representative example of this unbalanced knowledge about the siglec family, as this lectin has been barely documented in peer-reviewed publications over the last 15 years. This receptor suppresses antigen-specific T cell responses in tumoral environments as a result of T cell interaction with tumor-associated macrophages (TAMs), which overexpress sialylated glycans in their surface. Therefore, in the present project, we aim to characterize in detail the molecular basis for recognition of sialic acid-containing glycans by siglec-15 and find improved hits to efficiently target it (aim 1). Also, a second aim is to develop molecular conjugates containing siglec antigens (using these hits) to neutralize the inhibitory effect of both siglec receptors and PD-1 receptors, helping T cells to exert an effective immune response in tumoral environments (aim 2).
