To study immune suppression in advanced HPV+ cancers, Galliverti et al. used a nanoparticle-based E7 therapeutic vaccine in a human-mimicking cervical cancer GEMM with myeloid cell accumulation and poor DC and CTL function. The vaccine alone, or in combination with ICB, failed to increase CD8+ T cells in the TME. CD11b+ myeloid cells (monocytes; neutrophils could not be studied) in lymphoid organs were found to potently suppress CD8+ T cell proliferation and cytokine production, inhibit synergistic effects with ICB, and decrease APC function, suggesting that sustained depletion of myeloid cells might be beneficial in cancers with myeloid cell accumulation.
Contributed by Katherine Turner
Cancers induced by human papillomaviruses (HPV) should be responsive to immunotherapy by virtue of expressing the immunogenic oncoproteins E6/E7. However, advanced forms of cervical cancer, driven by HPV, are poorly responsive to immune response-enhancing treatments involving therapeutic vaccination against these viral neo-antigens. Leveraging a transgenic mouse model of HPV-derived cancers, K14HPV16/H2b, we demonstrated that a potent nanoparticle-based E7 vaccine, but not a conventional 'liquid' vaccine, induced E7 tumor-antigen-specific CD8+ T cells in cervical tumor-bearing mice. Vaccination alone or in combination with anti-PD-1/anti-CTLA4 did not elicit tumor regression nor increase CD8+ T cells in the tumor microenvironment (TME), suggesting the presence of immune suppressive barriers. Cervical cancer patients have poor dendritic cell functions, weak cytotoxic lymphocyte responses, and demonstrate an accumulation of myeloid cells in the periphery. Here, we illustrated that myeloid cells in K14HPV16/H2b mice possess potent immunosuppressive activity towards antigen presenting cells and CD8+ T cells, dampeing antitumor immunity. These immune-inhibitory effects inhibited synergistic effects of combining our oncoprotein vaccine with immune checkpoint blocking antibodies. Our data highlighted a link between HPV-induced cancers, systemic amplification of myeloid cells, and the detrimental effects of myeloid cells on CD8+ T cell activation and recruitment into the TME. These results established immunosuppressive myeloid cells in lymphoid organs as an HPV+ cancer-induced means of circumventing tumor immunity that will require targeted abrogation to enable the induction of efficacious anti-tumor immune responses.