HPV16-Expressing Tumors Release Multiple IL-1 Ligands to Orchestrate Systemic Immunosuppression Whose Disruption Enables Efficacy of a Therapeutic Vaccine

It is well-established that symptomatic cancers evade immune destruction by coalescing tumor microenvironments to suppress adaptive immunity. Additionally, mouse models of cervical and other cancers have revealed a capability of tumors to systemically induce the expansion of neutrophils that cripple T-cell development in spleen and lymph nodes, further impairing immune responses. Now we show that human papillomavirus type 16 (HPV16)–driven squamous cell tumors in the cervix and skin release into the circulatory system four immunoregulatory ligands – IL-1α, IL-1β, IL-33, and IL-36β – that bias the bone marrow toward granulocytic myelopoiesis, producing immunosuppressive neutrophils populating spleens and tumors. An IL-1 family coreceptor antagonist, anti-IL1RAP, abrogates this neutrophil expansion and complements an otherwise inefficacious HPV16 E7 peptide vaccine to elicit an effective antitumor immune response that is further sustained by anti–CTLA-4. Evidence for similarly IL-1–driven systemic immunosuppression in human cervical tumors encourages evaluation of this combinatorial therapeutic strategy for treating a largely immunoevasive cancer type. Significance: Cervical cancer is the fourth leading cause of cancer deaths in women worldwide. Although the disease is driven by two antigenic viral oncoproteins, therapeutic vaccines have proved ineffective, inferentially due to systemic immunosuppression. This study elucidated an actionable mechanism, whose disruption renders an oncoprotein vaccine efficacious, with translational potential.