Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

Abstract

The primary function of the immune system is to seek and eliminate altered or unhealthy cells. T cells are a major component of the immune response and mediate their functions by recognizing specific antigens that allow elimination of infected or neoplastic cells. To avoid inappropriate activation and subsequent immune injuries, T cells have evolved strategies to discriminate self from non-self, or healthy from altered and infected. These strategies rely on the activation of receptors that restrict the T cell response. CD33rSiglecs are a family of mostly inhibitory receptors that bind to sialic acids. Siglecs respond to specific sialic acid patterns characteristic for healthy and self and trigger tolerogenic signaling pathways that prevent activation of the immune response. To date the expression of Siglecs in human T cells is not well appreciated. We found that one Siglec member, Siglec-5, is transiently expressed only on activated T cells. Using overexpression studies, we showed that Siglec-5 is a strong inhibitor of T cell activation. The pattern of expression, along with the functional studies, suggested that Siglec-5 is a checkpoint-like receptor that negatively regulates T cell activation. Using a previously described protein ligand, we found that Siglec-5 activation reduces the T cells effector functions, as measured by production of cytokines and cytolytic molecules. Knowing from the literature that cancers change their sialyation to evade immune recognition, we hypothesized that Siglec-5 is a mechanism to enable this. We found that soluble Siglec-5 binds to cancer cell lines from different tissues, suggesting the expression of putative Siglec-5 ligands. Using engineered melanoma specific T cells, we measured the T cell specific response when the Siglec-5 signaling axis is interrupted. We found that blocking the availability of Siglec-5 putative ligands on the cancer cells reinvigorates the T cells immune response against melanoma cancer cells. Altogether, this work identifies Siglec-5 as a novel checkpoint receptor that suppresses the activation of T cells. Several checkpoint receptors with similar functions to Siglec-5 already serve as successful targets for cancer immunotherapies. However, such therapies work in only a small fraction of cancer patients. Our work shows that single agent blockade of Siglec-5 strongly reinvigorates the T cell response. Alone, or in combination with other checkpoint targets, blockade of Siglec-5 can serve as a strategy to prevent cancer immune evasion.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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