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Gene expression profiling of H16sc-IS1, Control H16sc-ImP and ILs-OE H16sc-ImP cancer cells.

ABSTRACT: It is well established that symptomatic cancers evade immune destruction by coalescing lesional and 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 myeloid cells that cripple T cell development in spleen and lymph nodes, further impairing immune responses. We show that HPV16-driven cervical cancers release into the circulatory system four immunoregulatory ligands – IL1α, IL1ß, IL33, and IL36ß – that bias the bone marrow toward granulocytic myelopoiesis, producing immunosuppressive neutrophils and myeloid progenitors differentially populating spleens and tumors to facilitate immune evasion. A pan-IL1 receptor antagonist, anti-IL1RAP, attenuates this myeloid expansion and complements an HPV-E7 peptide vaccine plus anti-CTLA4 to elicit anti-tumor immunity. Evidence for similar systemic activity of these four IL1 ligands in human cervical and other cancers encourages multi-targeting this signaling axis to broaden the scope of cancer immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE268239 | GEO | 2025/04/03

REPOSITORIES: GEO

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Gene expression profiling of neutrophils isolated from bone marrow, spleen and tumor of H16sc-IS1-tumor-bearing mice treated with anti-IL1RAP or untreated.

Project description:It is well established that symptomatic cancers evade immune destruction by coalescing lesional and 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 myeloid cells that cripple T cell development in spleen and lymph nodes, further impairing immune responses. We show that HPV16-driven cervical cancers release into the circulatory system four immunoregulatory ligands – IL1α, IL1ß, IL33, and IL36ß – that bias the bone marrow toward granulocytic myelopoiesis, producing immunosuppressive neutrophils and myeloid progenitors differentially populating spleens and tumors to facilitate immune evasion. A pan-IL1 receptor antagonist, anti-IL1RAP, attenuates this myeloid expansion and complements an HPV-E7 peptide vaccine plus anti-CTLA4 to elicit anti-tumor immunity. Evidence for similar systemic activity of these four IL1 ligands in human cervical and other cancers encourages multi-targeting this signaling axis to broaden the scope of cancer immunotherapy.

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Single cell transcriptomics of several organs in K14HPV16/H2b and FVBN/H2b mice.

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Gene expression profiling of neutrophils derived from K14HPV16/H2b and FVBN/H2b mice.

Project description:Cancers induced by human papillomaviruses should, in principle, be responsive to immunotherapy by virtue of expressing the immunogenic oncoproteins E6/E7 that drive malignancy. Rather, advanced forms of cervical cancer are poorly responsive to immune response-enhancing treatments involving therapeutic vaccination against these viral neo-antigens. Leveraging a transgenic mouse model for HPV-derived cancers, termed K14HPV16/H2b, we demonstrate that therapeutic vaccination with a nanoparticle-based vaccine alone or in combination with anti-PD-1/anti-CTLA4 does not elicit tumor regression nor increase the minimal CD8+ T cell infiltrates in the tumor microenvironment (TME), suggesting the presence of immunosuppressive barriers. We demonstrated that myeloid cells in lymphoid organs of K14HPV16/H2b mice possess potent immunosuppressive activity for both antigen presenting cells and CD8+ T cells that dampens the anti-tumor immune responsiveness. Our data highlight a link between HPV-induced cancers, systemic amplification of myeloid cells, and the detrimental effects of these cells on the generation of anti-tumor immune responses in the periphery, resulting in poor CD8 T cell activation and limited migration to the tumor site.

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