Effects of IL-17 neutralization in a murine model of HPV-positive head and neck squamous cell carcinoma

Presentation: S007
Topic: Cancer Biology
Type: Oral
Date: Sunday, July 9, 2023
Session: 10:45 AM - 12:15 PM Cancer Biology Session 1
Authors: Stephanie Wong, MD; Ruben Prins, MS; Martin Kast, PhD
Institution(s): University of Southern California

Background/Objective: Dysregulated IL-17 has been implicated in the development and progression of a variety of cancers, including those caused by high-risk human papilloma virus (HPV). While the exact mechanism of IL-17 tumorigenesis is unknown, studies have shown that IL-17 induces inflammatory mediators that increase recruitment of myeloid cells such as neutrophils and myeloid derived suppressor cells (MDSCs) that can collectively suppress the anti-tumor immune response. The presence of IL-17 has also been shown to suppress the therapeutic activity of HPV-specific vaccines in an HPV-positive murine model. The objective of this study was to characterize the changes in the tumor immune microenvironment (TIME) in response to IL-17 neutralization in a murine model of HPV-positive head and neck squamous cell carcinoma (mEER).

Methods: Twenty wild-type male C57BL/6 mice were implanted with 5x105 mEER cells in the right subcutaneous flank (day 0). The mice were separated into two groups of ten: the control group received PBS and the treatment group received IL-17 neutralization antibody. All mice were pretreated with PBS or IL-17 neutralizing antibody via intraperitoneal injection on days -3 and -2 prior to tumor implantation and twice weekly thereafter. Tumor size was measured using caliper measurements in three dimensions and calculated using length x width x depth. Tumor tissue and regional draining lymph nodes were harvested at the time of humane endpoint and immune cells were isolated from each sample. Immune cells were stained for separate lymphoid, myeloid, and T-helper subset panels and analyzed by flow cytometry. Percentages of different cell populations were compared using student’s t-test and significance was determined by p < 0.05.

Results: Tumor growth overall was slower in the IL-17 neutralization group compared to the PBS control group (p < 0.05). Intratumorally, the treatment group showed decreased CD8+ T cells (31% vs 23%, p < 0.01) and increased CD4+ T cells (42% vs 49%, p = 0.0584). The same pattern was observed in the draining lymph nodes, with the treatment group showed increased CD4+ T cells (p < 0.05) and decreased CD8+ T cells (p < 0.05). Of the CD4+ T cells, the proportions Th1, Th2, and Th17 cells were all significantly decreased in the treatment group (p < 0.05). Intratumoral MDSCs (26% vs 18%) and neutrophils (24% vs 17%) were decreased in the treatment group, however the differences were not significant (p = 0.0725 and p = 0.0783, respectively).

Conclusions: IL-17 neutralization in vivo decreases tumor growth in a mouse model of HPV-positive head and neck cancer. Our results also demonstrate that IL-17 neutralization causes significant differences in the proportions of various immune cell populations within TIME. Further studies are required to determine the mechanism by which IL-17 neutralization alters the TIME, however these results make IL-17 neutralization a promising adjuvant treatment for HPV-positive head and neck cancer.