Importance of Specific NK Cell Subsets for Antitumor Immunity in HPV+ Cancers

High-risk type human papillomaviruses (HPV) are associated with genital and oral cancers, and the incidence of HPV+ head and neck squamous cell cancers is fast increasing worldwide. Survival rates for patients with locally advanced disease are poor and variable after standard of care (SOC) treatment. Identifying the antitumor host immune mediators important for treatment response and designing strategies to promote them are essential for improving clinical outcome. The natural killer (NK) cells are a critical component for antitumor innate effector immunity. Among the multitude of activation and inhibitory receptors on immune cells, HLA-DR is recognized as an important activation marker on both CD8 T and NK cells. Literature studies refer to HLA-DR+ NK cells as pre-mNK. Data from our preclinical HPV tumor models demonstrated that induction of the pre-mNK equivalent NK subset known in literature as natural killer dendritic cells (NKDC), a novel NK subset expressing the DC marker CD11c, via therapeutic HPV peptide vaccination, contribute to tumor-free long-term survival. 

In addition to antigen-specific CD8 T cell responses, overall innate immune effector responses, including polyfunctional NKDC, were elevated in mice treated with and HPV peptide therapeutic vaccine containing the combination of QS21 and CpG adjuvants (TVQC). Further, the CD11c+ NK subset (NKDC) exhibited higher functionality compared to the CD11c- NK subset, further highlighting the importance of NKDC for vaccine mediated immunity. In the clinical setting, we evaluated pre-mNK in HPV+ cancer patients, compared to healthy donors, and detected dysfunctional circulating pre-mNK in terms of increased inhibition indicated by PD-1 expression and reduced cytotoxic potential, indicated by lower levels of granzyme B (GrnzB) and CD16, an NK receptor important for Antibody Dependent Cellular Cytotoxicity (ADCC). In HPV+ head and neck patients, post-SOC, the circulating pre-mNK cells exhibited significant increases in GrnzB and CD16, indicating elevated cytotoxic potential after treatment. In cervical cancer patients, we analyzed the tumor microenvironment (TME) using non-invasive cytobrush sampling and found a significantly increased frequency of cytotoxic pre-mNK cells post-treatment that was not discernible in circulation. Employing clinically applicable cytokines we achieved significant ex vivo expansion of highly cytotoxic pre-mNK populations useful for adoptive cell therapy applications. These results emphasize the importance of pre-mNK subset of NK cells for protection in HPV cancers.

Advisory Committee:
Jagannadha Sastry, PhD, Chair
Gheath Al-Atrash, DO, PhD
Tina Cascone, MD, PhD
Maura Gillison, MD, PhD
Ann Klopp, MD, PhD

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