Publication Date

2014-02-10

Availability

Embargoed

Embargo Period

2016-02-10

Degree Type

Doctoral Essay

Degree Name

Doctor of Philosophy (PHD)

Department

Microbiology and Immunology (Medicine)

Date of Defense

2014-02-06

First Committee Member

Zhibin Chen

Second Committee Member

Rebecca Adkins

Third Committee Member

Balakrishna Lokeshwar

Fourth Committee Member

Eli Gilboa

Fifth Committee Member

Geoffrey Stone

Sixth Committee Member

Priyamvada Rai

Abstract

The difficulty in identifying a tumor-specific antigen (TSA) in a majority of tumors poses a clinical problem in treating cancer with immunotherapy. To date, the majority of tumor antigens identified are not tumor-specific, but are rather largely “self” in nature, and the destruction of these tissues appear to be similar to autoimmune damage of normal tissues. Indeed, clinical studies of successful immune checkpoint therapies like such as anti-CTLA4 and anti-PD1/PD-L1 antibody treatment revealed a strong association of autoimmune side effects with therapeutic benefit. In these cases the anti-tumor effect seems to be mediated by, in part, an autoimmune response. The potential interrelatedness of autoimmunity and anti-tumor immunity indicates that the autoimmune process can be used as a potential tool for the destruction of tumor tissue. Further evidence is derived from genetic polymorphisms that alter CTLA4 expression in humans. CTLA4 polymorphisms that cause a reduction in its expression are associated with both a significant increase in autoimmune risk and a decrease in the risk of certain cancers. However, quite perplexingly, the same CTLA4 polymorphisms also are associated with increased risk of gastrointestinal carcinogenesis. These previous studies suggest that regulators of autoimmunity have both pro- and anti-tumor capability depending on the context in which it is studied. To address these questions, we examined the mechanisms of the critical immune checkpoint regulator CTLA4 in the context of autoimmunity, anti-tumor immunity, and tumorigenesis. We first characterized the behavior of autoimmune cells directly in the target tissue utilizing intravital microscopy. By using the anterior chamber of the eye as a “window” to the live tissues, we could visualize the behavior of TCR restricted (BDC2.5) autoimmune T-effector (Teff) and T-regulatory (Treg) cells in protection and rejection of islet grafts. Teff and Treg directly contact one another, and this contact is essential in protecting islet grafts from autoimmune destruction. In a separate model, we demonstrate islet grafts that are directly adjacent to target islets proliferate rapidly as a result of CD8+ mediated destruction of the target. Both of these observations are critical to our understanding of autoimmunity. To study the potential role of autoimmune effectors in anti-tumor immunity, we transplanted tumor cells into mice bearing the same autoimmune targets as the endogenous pancreas. After the injection of autoimmune effectors, both the endogenous pancreas and tumor were completely destroyed. The inclusion of a suboptimal amount of Treg restored protection to the tumor but not the endogenous pancreas. Anti-CTLA4 could overcome this protective effect, suggesting that Anti-CTLA4 antibody therapy works, in part, by inducing an autoimmune mediated antitumor response. The data from these experiments suggest the autoimmunity can play a force in anti-tumor immunity, and CTLA4 can regulate this response. Since small changes in CTLA4 expression can dramatically change the outcome of an anti-tumor response, we generated CTLA4 RNAi mice. These mice have reduced CTLA4 expression that is comparable to reductions caused by promoter polymorphisms in humans. Astoundingly, these mice uniformly develop gastric metaplastic pathology by 5 weeks of age; a process initiated by an inflammatory autoimmune response. This pathology persisted until 17-18 months of age, at which point the gastric metaplasia progressed into adenocarcinoma. An age associated increase in tumor protective 5-hmC epigenetic modification occurs in wildtype mice, which did not occur in the CTLA4 RNAi mice; a finding extended to human adenocarcinoma. The data from these experiments demonstrate the complicated and sometimes paradoxical role of T-cells in autoimmunity and tumor immunity. A better understanding of these mechanisms will lead to new insights on how to: restore immunological balance in individuals with autoimmunity; harness the immense power of the immune system to eradicate tumors; and prevent inflammation induced tumorigenesis.

Keywords

Tumor Immunology; Inflammation; Autoimmunity; Intravital Imaging

Video 1.mpg (276 kB)
Video 2.mpg (4348 kB)
Video 3a.mpg (552 kB)
Video 3b.mpg (702 kB)

Share

COinS