The curdlan and/or anti-VISTA monoclonal antibody enhances innate and adaptive immune responses in the mouse model of melanoma

  • Author / Creator
    Mashhouri, Siavash
  • During the past decade, the field of immuno-oncology has been revolutionized by the emergence of immune checkpoint inhibitors (ICIs). However, acquired resistance to ICIs and relapse after immunotherapy are associated with defects in antigen presentation and the upregulation of exhaustion ligands in tumours. Therefore, identifying new approaches to overcome these barriers is crucial to improve the quality of life and increase the survival rate in cancer patients. Dendritic cell-associated C-type lectin-1 (Dectin-1) is a C-type lectin receptor best known for its ability to recognize β-glucan-rich structures in fungal cell walls. Dectin-1 is expressed in myeloid cells and tumour cells, however, its role in cancer has been the subject of debate and controversy. Therefore, I decided to investigate the role of Dectin-1 in B16-F10 melanoma and CT26 colorectal tumour models. I found that myeloid cells were the most dominant cells in terms of Dectin-1 expression. In particular, I found that Dectin-1+ myeloid cells exhibited an activated phenotype characterized by elevated levels of CD80, CD86, and MHC Class II levels in the tumour microenvironment (TME). For the very first time, based on my knowledge, observed a strong co-expression/co-localization of Dectin-1 with V-domain Ig suppressor of T cell activation (VISTA), Programmed death-ligand 1 (PD-L1), Programmed death-ligand 1 (PD-L2), and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) in myeloid cells from the TME versus spleen in tumor-bearing mice. Our results indicated that Dectin-1 is commonly expressed by active tumor-associated myeloid cells. However, I found significantly greater levels of Dectin-1 at the gene and protein levels in myeloid cells from the B16-F10 model. Therefore, I decided to further investigate the role of Dectin-1 in the B16-F10 model by deleting this molecule (using Dectin-1 knockout) or stimulating Dectin-1 by treating mice with curdlan (a β-glucan ligand. Although Dectin-1 deletion had no effects on tumor progression, curdlan treatment significantly enhanced the innate and adaptive immune responses resulting in reduced tumor progression. Therefore, Dectin-1 stimulation could be considered a potential target concurrent with ICIs since it engages innate and adaptive immune responses. These results provide more justification for designing novel immunotherapy strategies by reprogramming the TME to target both arms of the immune system.

  • Subjects / Keywords
  • Graduation date
    Spring 2022
  • Type of Item
  • Degree
    Master of Science
  • DOI
  • License
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