Dissertations and Theses (Open Access)

Date of Graduation

8-2026

Document Type

Thesis (MS)

Program Affiliation

Immunology

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Dr. Michael A. Curran

Committee Member

Dr. Pamela L. Wenzel

Committee Member

Dr. Simon W. Young

Committee Member

Dr. Matthew M. Gubin

Committee Member

Dr. Ann H. Klopp

Abstract

Human papillomavirus (HPV) infection has been known to be a contributing factor in the development of several malignancies, including anal, vulvar, cervical, penile, and oropharyngeal cancers. Persistent HPV infections are strongly associated with the development of cervical cancer in women, but due to the widespread screening programs and the increased use of prophylactic HPV vaccines, incidences of cervical cancer in women over the last few decades have steadily declined. In contrast, the incidences of human papillomavirus (HPV) – driven malignant HNSCC cancers, particularly oropharyngeal squamous cell carcinoma, have risen steadily, with a disproportionately higher incidence seen in men. Recent advancements in cancer immunotherapy have demonstrated the clinical efficacy of immune checkpoint inhibitors, including ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1), in preventing the engagement of co-inhibitory receptors that suppress immune activation. Blockade of CTLA-4 receptor with anti-CTLA-4 antibody (ipilimumab) releases the immune “brakes” by blocking inhibitory signaling pathways, resulting in enhanced activation and cytotoxic function of both T cells and natural killer (NK) cells.

Natural killer (NK) cells are a small subset of lymphocytes and mediators of antibody – dependent cellular cytotoxicity (ADCC). Clinical findings from the phase I/II INVAX trial (Ipilimumab/Nivolumab and Volume Adaptation of XRT) identifies a subset of exceptional

responders to anti-CTLA-4 therapy characterized by increased intra-tumoral infiltration of cytotoxic CD8+ T cells and NK cells. These responses were associated with the selective depletion of immunosuppressive 4-1BB+ regulatory T cells (Tregs) through natural killer (NK) cells antibody-dependent cellular cytotoxicity (ADCC), subsequently enhancing CD8+ T cell infiltration into the tumor microenvironment. Immunotherapeutic approaches that enhance NK cell activity may improve antibody-mediated antitumor immunity and improve therapeutic outcomes. Based on these observations, we hypothesize that increased NK cells infiltration within the tumor microenvironment of HPV+ HNSCC facilitates anti-CTLA-4 mediated depletion of 4-1BB+ Tregs through ADCC mechanisms, thereby promoting enhanced CD8+ T- cell infiltration, activation, and antitumor function. Understanding the immunologic relationship between NK cells, Tregs and checkpoint blockade therapy may provide insight into mechanisms underlying therapeutic responsiveness and support the development of more effective immunotherapeutic strategies for treating HPV+ HNSCC.

Keywords

Human Papillomavirus, Cytokine, INVAX, Xencor, Natural Killer Cells, Tregs, ADCC, CTLA-4

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Available for download on Thursday, August 12, 2027

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