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Dissertation/Thesis Abstract

Influenza A Viruses as Drivers of Anti-viral and Anti-tumor Immune Responses
by Hamilton, Jennifer R., Ph.D., Icahn School of Medicine at Mount Sinai, 2018, 135; 10749278
Abstract (Summary)

Influenza A virus (IAV) infection stimulates host anti-viral immune responses. This includes induction of innate anti-viral responses—which work early during infection to limit viral replication and spread—as well as long-lasting, antigen-specific, adaptive immune responses. The generation of adaptive B and T cells in response to IAV infection is well understood, and these are required for the clearance of IAV infection. This thesis addresses two major questions about the immunity induced by IAV infection. First, are there unexplored mechanisms of immunity elicited by IAV infection beyond the well-characterized B and T cell responses? And second, can we utilize our understanding of the relationship between IAV and the immune system to intentionally drive anti-tumor responses in the context of cancer?

To the first question, it has been observed that, following IAV infection, the host is protected from subsequent unrelated respiratory virus infections for a period of time. This observation runs contrary to our understanding of classical adaptive immune responses: this temporary nonspecific protection is neither explained by cross-reactive adaptive responses, nor prolonged interferon signaling. However, we have discovered a population of respiratory club cells (formerly known as Clara cells) that survive direct infection with IAV. Survival of IAV infection results in the “reprogramming” of these cells to an anti-viral response phenotype. Moreover, depletion of these cells abrogates the temporary non-specific immunity elicited following IAV infection, thus demonstrating the importance of cells surviving influenza virus infection as a mechanism for preventing viral diseases.

Additionally, IAV has been studied as an oncolytic agent because of its capacity to lyse tumor cells. We reasoned that intra-tumoral injection of IAV would directly lyse tumor cells as well as promote an anti-tumor adaptive immune response. To further promote an anti-tumor response, we engineered an IAV to express an antibody that inhibits the immune checkpoint CTLA4, (IAV-CTLA4). In the B16 mouse melanoma model, we found that IAV-CTLA4 potently delays tumor growth compared to mice administered unmodified IAV or vehicle control. Moreover, IAV-CTLA4 promotes a modest abscopal effect by delaying the growth of anatomically distant, untreated tumors, as well as enhancing overall survival.

Together, this thesis demonstrates that it is possible for IAV infection to promote desirable immune responses: either non-specific anti-viral protection or systemic anti- tumor effects. Findings discussed herein may inform future vaccine designs—where eliciting nonspecific immunity would be beneficial—or novel oncolytic viral therapies.

Indexing (document details)
Advisor: Palese, Peter
Commitee: Dermody, Terence S., Evans, Matthew J., Fernandez-Sesma, Ana, Lee, Benhur, tenOever, Benjamin R.
School: Icahn School of Medicine at Mount Sinai
Department: Microbiology
School Location: United States -- New York
Source: DAI-B 79/08(E), Dissertation Abstracts International
Subjects: Bioengineering, Virology, Immunology
Keywords: Immune responses, Influenza A
Publication Number: 10749278
ISBN: 978-0-355-83952-4
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