The Role of AIM2 During Head and Neck Cancer Development and Its Role in Antigen Specific Activation of CD4 T cells

Abstract

The immune system is a vital part of mammalian biology that works to protect the individual from microbial invasion and neoplastic transformations. In particular, the immune system plays a complex role during cancer development, promoting anticancer responses, but can also promote cancer under certain contexts. Chronic inflammation is one of the emerging mechanisms by which the immune system can drive cancer development. Pattern recognition receptors (PRRs), like Absent in Melanoma 2 (AIM2), initiate inflammatory responses. Several PRRs have been implicated in cancer development and other inflammatory diseases. AIM2 also acts as a tumor suppressor, helping to restrict cancer development. AIM2 also regulates the differentiation of T cell subsets, which are vital for mounting anti-cancer immune responses. Head and neck cancer is heavily associated with chronic inflammation and immune dysregulation. Survival rates for head and neck cancer patients have not improved in the past decade. The role of the immune system during the early developmental stages of head and neck cancer remains largely unknown. Thus, it is important to investigate the role of the immune system during the development of head and neck cancer. This dissertation outlines two novel roles for AIM2 in the immune system. The first is AIM2’s ability to restrict head and neck cancer development. I discovered that AIM2 restricts tumor sizes in mice during 4NQO-induced head and neck cancer. AIM2 also restricts interferon gamma (IFN-γ) and IFN-γ-associated gene signature in the tongues of 4NQO-treated mice and limits the infiltration of macrophages into the tongue tissue. Also, AIM2’s ability to restrict tongue tumor sizes was dependent on the adaptive immune compartment. This study illuminates a novel role for AIM2 during head and neck cancer development. The second major finding described in this dissertation focuses on the intrinsic role of AIM2 in CD4 T cells during antigen-specific activation and differentiation. Studies have revealed conflicting data on AIM2’s role in Th17 and regulatory T cell differentiation. Also, these studies that explored AIM2’s role in T cell differentiation failed to use antigen-specific model. To address this, we crossed AIM2 deficient mice with animals expressing an ovalbumin specific T cell receptor in CD4 T cells (OT-II). We found that AIM2 does not regulate thymic selection but found fewer recent thymic emigrants to the spleen and fewer CD4 T cells in the spleen of AIM2 deficient OT-II mice. This suggests AIM2 impacts either CD4 T cell migration, retention or homeostasis in secondary lymphoid organs of mice. I further investigated if AIM2 plays a role during antigen-specific activation of CD4 T cells in vitro and found that Aim2-/- OT-II CD4 T cells produce less IL-2 than wild type OT-II CD4 T cells when co-cultured with ovalbumin-incubated dendritic cells. However, we assessed Aim2-/- OT-II CD4 T cell proliferative capacity and differentiation ability in response to OVA immunization in vivo and found no difference between WT OT-II CD4 T cells. Finally, we assessed Aim2-/- OT-II CD4 T cell functional ability utilizing an in vivo syngeneic tumor injection model where B16-OVA melanoma or NOOC2-OVA cancer cells were injected into the flanks of mice and WT or Aim2-/- OT-II cells were transferred into the mice and the tumors were measured over one month. We found no difference in tumor growth between mice that received WT or Aim2-/- OT-II cells. Thus, this deficiency in IL-2 production in Aim2-/- OT-II cells does not result in differentiation differences or functional differences. Further studies are needed to determine how AIM2 regulates CD4 T cell homeostasis and IL-2 production. Taken together, my results and others indicate that AIM2 plays a complex role during head and neck cancer development and T cell biology.