The immune landscape is a strong predictive biomarker for clinical outcome in early stage vulvar cancer, irrespective of HPV or p53 status

Introduction/Background Vulvar squamous cell carcinoma (VSCC) consists of three subtypes; HPV-related, HPV-negative TP53 wildtype and HPV-negative mutated TP53 (HPVposVSCC, HPVnegVSCC/p53wt, and HPVnegVSCC/ p53abn, respectively) which are all treated by mutilating radical surgery and/or (chemo)radiotherapy. Despite the fact that the immune system plays a key role in cancer, the knowledge on its effect in VSCC is limited at best. A study, elucidating the clinical impact of tumor-immunity in VSCC was, therefore, performed with the aim to foster the development of immunotherapeutic approaches. Methodology Sixty-five patients with early-stage VSCC were categorized based on HPV and p53 status. Archived tissues were analyzed for expression of CD3, CD8, FoxP3, PD-1, and pan-keratin in randomly selected areas using immunofluorescence. Additional phenotyping of T cells was performed exvivo on VSCC and blood samples by flow cytometry. Healthy vulvar tissue and blood served as controls. Results T-cell infiltration of VSCC was highly variable between patients, ranging from completely absent to very high numbers, and differed per VSCC subtype. Approximately 80% of the HPVposVSCC showed high T-cell infiltration, followed by 60% of the HPVnegVSCC/p53wt, and 40% of the HPVnegVSCC/p53abn. Importantly, high T-cell infiltration was associated with longer recurrence-free period and overall survival, irrespective of the HPV and p53 status. In-depth analysis of tumor-infiltrating T cells with flow cytometry confirmed the tumor-specific presence of activated effector memory T cells in VSCC and revealed that most of the CD4+ and CD8 + T cells expressed PD-1. Conclusion This study is the first to show a strong correlation between T-cell infiltration and clinical outcome. Our data suggest the application of two immunotherapeutic strategies depending on immune phenotype. The high expression of PD- 1 in T-cell infiltrated tumors alludes to anti-PD1 blockade, whereas VSCC tumors with low numbers of intratumoral T cells should be stimulated with inflammatory reagents to stimulate local immune responses.