5-azacytidine promotes immune recognition and T cell infiltration in HPV-positive head and neck squamous cell carcinoma patients

Presentation: P011
Topic: Cancer Biology
Type: Poster
Authors: Jason Tasoulas, MD, DMD1; Andrew Sewell, MD, PhD1; Hina Rehmani, PhD1; David Rimm, MD, PhD2; Karen S Anderson, PhD2; Barbara Burtness, MD2; Wendell G Yarbrough, MD, MMHC, FACS1; Natalia Issaeva, PhD1
Institution(s): 1University of North Carolina at Chapel Hill; 2Yale University

Background: HPV-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) is generally highly treatment responsive, but 20% of patients recur. Of these, the majority are not cured even in the era of immune checkpoint inhibition (ICI), due to de novo or acquired resistance. While The Cancer Genome Atlas project provided insights into potential vulnerabilities of HPV+ HNSCC, many of these are yet to be translated into clinically useful tools. HPV+ HNSCC has a distinct hypermethylation pattern that silences immune response genes and inhibits immune recognition. However, it is unclear whether demethylation can affect tumor cell viability, tumor immune infiltration, or response to ICI.

Patients and Methods: We used preclinical models and samples from a pre-operative 5-azacytidine (5-azaC (75mg/m2/d x 5)) window trial to evaluate the effects of 5-azaC treatment on immune recognition of HPV-associated head and neck tumors.

Results: Demethylating therapy with 5-azaC (1) activated type I interferon response, (2) upregulated and activated the mutagenic cytidine deaminase APOBEC3B, (3) increased expression of several neoantigens, (4) dramatically increased expression of antigen processing and presentation genes, and (5) promoted activated T cell infiltration within HPV+ tumors. These results prompted the design and approval of a 3-arm pre-operative window trial to evaluate treatment response to and immune effects of 5-azaC, or nivolumab, or the combination in treatment-naïve HPV+ HNSCC.

Conclusion: Because T cell infiltration is an absolute requirement for effective response to ICI, the combination of 5-azaC with anti-PD1 agents like nivolumab may enhance response to ICI and overcome resistance to ICI therapies in HPV+ HNSCC patients. This combination will be evaluated in a window clinical trial.