Ephraim, Ramya (2023) Checkpoint and inflammatory markers in chronic colitis and colorectal cancer. Research Master thesis, Victoria University.

Abstract

Cancer immunotherapy has evolved major breakthroughs in the last years and since then, it has subsequently been developed into a novel method for treating cancer through boosting the immune system, rather than using chemotherapeutic agents to directly attack the tumour cells. This treatment can be broadly classified either as cancer vaccines, adoptive cellular immunotherapy, or therapies using immune checkpoint blockades. These markers which are expressed on cancer cells to be used as an escape mechanism from the immune system, have revolutionised cancer treatment in recent years. Immune checkpoint inhibitors (ICI), in single agent and combination regimens, have produced durable and long-lasting clinical responses. The ICIs developed against cytotoxic T-lymphocyte–associated antigen 4 (CTLA4) and Programmed death 1 (PD1), block immune-inhibitory receptors on activated T-cells, amplifying immune responses. . Inflammatory Bowel Disease (IBD) refers to a group of disorders that cause chronic gastrointestinal inflammation including Crohn’s disease (McDaniel et al.) and ulcerative colitis (UC), not only the chronic colitis. The current available treatments for chronic colitis include corticosteroids, anti-inflammatories and antibiotics that reduce non-specific inflammation with the aim to decrease relapse rates, however, such treatments are ineffective in the long term. Patients with chronic colitis are at increased risk for developing colorectal cancer (CRC) with longer duration, extent of colitis and a familial history of CRC. Checkpoint markers are expressed on cancer cells as an escape mechanism from the immune system and checkpoint inhibitors have revolutionized cancer treatment in recent years. There is often a limit in using chemotherapy due to the side effects that leads to reduced efficacy, which leads to an urgent need in improving treatments, identifying new targets and the action mechanisms of those targets in cancer progression. Winnie mouse and severely inflamed Winnie prolapse mice are a viable model of spontaneous chronic inflammation with immune responses similar to human chronic colitis. Determining the level of checkpoint markers in these mice tissues will provide insights into disease initiation and progression and to identify novel targets for new therapeutics design. In this study we were interested in checkpoint and inflammatory markers, as well as identification of early CRC gene markers in IBD by using Next Generation Sequencing (NGS) to search for different genetic alterations that originate in colon segments. The overall aim of this study is to analyse the up and down regulated genes and study the pathways in Winnie mice and Winnie prolapse mice when compared with the C57BL/6 mice. Based our overall study and analyses of genes and pathways it was identified that the cancer related genes and pathways that were highly enriched in Winnie prolapse mice when compared to Winnie mice which could lead to the fact that inflammation may be linked to cancer or pre-cancerous stages. Further study of these checkpoint markers could lead to the development of biomarkers for chronic colitis patients, as well as a better knowledge of inflammation and cancer, which could lead to the development of treatments that use biomarker expression inhibitors or vaccinations to prevent disease progression.

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