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Targeting sialoglycan – Siglec Interactions in Cancer Immunology

Stanczak, Michal Adam. Targeting sialoglycan – Siglec Interactions in Cancer Immunology. 2020, Doctoral Thesis, University of Basel, Faculty of Science.

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Abstract

Cancer is one of the leading causes of death worldwide. While advances in basic cancer biology have vastly increased our knowledge and guided the development of new, genomically targeted therapies, resistance occurs frequently and leads to disease progression in the majority of patients. The translation of basic research regarding the regulation of T cell responses into the clinics have ultimately resulted in the development of immunotherapy with immune checkpoint inhibitors. While this has significantly improved the outcome of cancer therapy and led to durable responses and long-term survival in a subset of patients, the majority of patients still derives no benefit from immunotherapy, emphasizing the need for the development of novel approaches.
Hypersialylation of tumor cells and the tumor microenvironment was recently shown to be a targetable pathway of adaptive immune escape in cancer. CD33-related Siglecs are sialic acid binding receptors, that function as pattern recognition receptors for self-associated molecular patterns and modulate immune responses. While Siglecs are expressed to very low levels on normal T cells, we were able to show their functional upregulation of tumor-infiltrating T cells in several human cancers. Siglec-9 expressing T cells co-expressed high levels of inhibitory receptors including PD-1, yet were functional and could be further reinvigorated by blocking of sialoglycan-Siglec-9 interactions. Due to the high degree of redundancy in sialoglycan- Siglec interactions, an approach aiming to desialylate the tumor microenvironment in a targeted way was pursued, removing a broad range of ligands instead of blocking individual Siglecs. We show that targeting sialidases by fusion to tumor-specific antibodies such as Trastuzumab is feasible and results in pronounced desialylation in vivo. Targeted-sialidase treatment demonstrated single agent efficacy in different preclinical mouse models, induced to intratumoral T cell activation and tumor rejection, as well as the generation of a T cell memory response through a Siglec-dependent mechanism. Both therapeutic and genetic models of desialylation synergized with checkpoint blockade and led to increased tumor control in mice. Analysis of TCGA datasets enabled the definition of a gene expression signature of tumor hypersialylation, correlating inversely with survival in several cancers, in particular lung squamous cell and clear cell renal carcinoma, as well as with several indicators of an increased immunosuppressive microenvironment and T cell dysfunction.
Taken together, the sialoglycan-Siglec pathway is identified as a new target for immunotherapy and systemic targeting of tumor hypersialylation shown to be efficacious in vivo and synergizing with immunotherapy, providing rational basis for future clinical development.
Advisors:Pieters, Jean and Zippelius, Alfred and Hennet, Thierry
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Infection Biology > Biochemistry (Pieters)
UniBasel Contributors:Pieters, Jean and Zippelius, Alfred
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13966
Thesis status:Complete
Number of Pages:157
Language:English
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss139667
edoc DOI:
Last Modified:11 Mar 2021 09:49
Deposited On:01 Mar 2021 15:53

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