The contribution of Sting and Nlrp3 activation to anti-tumour immunity in microsatellite instable colorectal cancer

• Author / Creator

  Mowat, Courtney V.

• The constant exposure of the intestine to antigens forces the mucosal immune system to be tolerant to avoid a constitutively inflamed state. Unfortunately, immune tolerance can allow colorectal cancers (CRCs) to escape detection. The majority of CRCs are chromosomally instable (CIN) and display the features of an immune ignorant tumour, including the exclusion of cytotoxic T cells (CD8+). Nonetheless, approximately 15% of all CRCs are microsatellite instable (MSI) and have high infiltrating CD8+ T cells and a more favourable prognosis as a result. A prevailing hypothesis to explain MSI CRC’s enhanced immunogenicity stems from hypermutability driving the accumulation of tumour associated antigens that stimulate an adaptive immune response. Although this is agreed to be a contributing factor, it is likely not the only influence because not all hypermutable tumours have enhanced anti-tumour immunity. One alternative explanation is that different defective DNA repair pathways may influence the growth of specific intestinal bacteria, driving immunogenicity. A major way intestinal epithelial cells communicate with microbes is through pattern recognition receptors (PRRs), including NLRP3 and STING, which have higher expression in MSI compared to other CRCs. We suspect that the activity of such receptors is aiding in MSI CRC’s better prognosis, either by recruiting cytotoxic immune cells, or by inducing programed tumour cell death. We sought to determine if MSI CRCs have altered bacteria recognition when compared to CRCs with other types of genetic instability, and if this could impact the anti-tumour immune response. We discovered that cooperation between NLRP3 and STING signaling aids in MSI CRC’s enhanced prognosis, thereby identifying new possible therapeutic targets to enhance anti-tumour immunity and immunotherapy responsiveness in the more aggressive CIN CRCs.

• Subjects / Keywords

  • Nlrp3
  • Pattern Recognition Receptors
  • Immunology
  • Sting
  • Colorectal Cancer

• Graduation date

  Fall 2019

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-jywj-nr54

• License

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