Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Microbiology and Immunology

Supervisor

Gunaratnam, Lakshman

Abstract

T cell immunoglobulin and mucin domain-1 (Tim-1) is expressed by CD4+ T cells, invariant natural killer T (iNKT) cells, and regulatory B cells (Bregs). Tim-1 expression on CD4+ T cells and iNKT cells typically promote proinflammatory responses, while Tim-1-expressing Bregs are immunosuppressive. However, the potential role of Tim-1 in anti-tumour immunity is unclear. To investigate the effects of Tim-1 on B16F1 melanoma and MC38 colorectal adenocarcinoma models, I compared tumour growth and survival between Tim-1-expressing (wild-type) and Tim-1-deficient mice. Using B16F1 melanoma, I demonstrated that Tim-1-deficient mice exhibited delayed tumour growth and improved survival, compared to wild-type mice. When immunized with heat-killed B16F1 melanoma cells, decreased frequencies of Bregs were found in Tim-1-deficient mice. These data suggest that Tim-1 expression may promote tumour growth by inducing Bregs. Therefore, anti-cancer treatments aimed at suppressing the function of Tim-1-expressing Bregs may be of therapeutic value.

Summary for Lay Audience

Cancer is a disorder that describes abnormal cell growth or tumours that can interfere with the growth and development of normal cells. The high prevalence and mortality rate of cancer makes it a serious global burden. Throughout the years, various therapies have been developed to treat cancer, but curative therapies remain elusive for most cancers, including colon cancer and melanoma (skin cancer). The immune system plays a key role in detecting and eliminating cancer throughout life. Developing immunity against cancer (anti-cancer immunity), much like immunity against viruses, has the potential to be curative. While immune cells utilize a variety of mechanisms to kill cancer cells, the existence of cancer cells indicates that cancer cells learn to evade the host’s immune system. Cancer cells can escape the immune system by preventing detection or infiltration of immune cells, or by inhibiting the function of immune cells that have infiltrated the tumour. In addition, cancer cells can recruit immune cells that modulate and suppresses the immune system. Therefore, further understanding the workings of anti-cancer immunity may lead to potentially curative cancer therapies. This study focuses on T cell immunoglobulin and mucin domain-1 (Tim-1). Tim-1 is a protein found in some important anti-cancer immune cells. However, the role of Tim-1 in anti-cancer immune responses is unclear. In this study, I tested the effect of host Tim-1 on cancer growth and survival by implanting mouse colon or melanoma tumours into normal mice or mice lacking the gene for Tim-1. I found that mice lacking the Tim-1 gene have improved survival and delayed tumour growth, compared to mice expressing the Tim-1 gene. As well, examination of anti-cancer iv immune responses in the mice lacking Tim-1 revealed that they have fewer B cells, a type of immune cell. I conclude that host Tim-1 impairs anti-cancer immune responses. Furthermore, the inhibition of host Tim-1 on B cells may be a new strategy for improving or augmenting host anti-cancer immune response in patients.

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