Combination of HDAC inhibition and cytokine enhances therapeutic HPV vaccine therapy
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ABSTRACT:
PROVIDER: PRJNA1253744 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33241300.fastq.gz | Fastqsanger.gz | |||
| SRR33241301.fastq.gz | Fastqsanger.gz | |||
| SRR33241302.fastq.gz | Fastqsanger.gz | |||
| SRR33241303.fastq.gz | Fastqsanger.gz | |||
| SRR33241304.fastq.gz | Fastqsanger.gz |
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Project description:HPV-associated malignancies continue to present a major health concern despite the development of prophylactic vaccines. Standard therapies offer limited benefit to patients with advanced stage disease. Despite improved outcomes with PD-1 targeted therapies, treatment resistance and modest response rates highlight a significant unmet need to develop novel therapies for these patients. PDS0101 (designated HPV vaccine) is a liposomal nanoparticle HPV16-specific therapeutic vaccine that has been shown to generate strong HPV-specific responses in pre-clinical and clinical studies. Here we assess the efficacy of this HPV vaccine in combination with the tumor-targeting immunocytokine NHS-IL12 (PDS01ADC), plus either aPD-1 or the class I histone deacetylase (HDAC) inhibitor Entinostat. Mice bearing HPV16+, aPD-1 refractory TC-1 and mEER tumors were treated with HPV vaccine, NHS-IL12, and either aPD-1 or Entinostat to determine anti-tumor efficacy and survival benefits. A comprehensive analysis of the tumor microenvironment was performed using flow cytometry, multiplex immunofluorescence, chemokine and cytokine assessment, and scRNAseq with TCR enrichment. Combination of HPV vaccine and NHS-IL12 with either Entinostat or aPD-1 yields significant anti-tumor activity and prolonged survival in aPD-1 refractory models of HPV16+ cancer, with superior activity employing Entinostat versus aPD-1 combination. Entinostat triple therapy increased overall and HPV16-specific tumor CD8+ T cell infiltration with heightened cytotoxicity. TCR sequencing revealed a CD8+ T cell clone unique to vaccine-treated cohorts, which displayed an enriched cytotoxic transcriptional profile with triple therapy. These effects were parallelled by strong differentiation of tumor-associated macrophages (TAMs) towards proinflammatory, anti-tumor M1-like cell states. Single-cell transcriptomic analysis indicated all three agents were required for highest modulation of both CD8+ T cells and TAMs conducive to tumor control. A biomarker signature reflecting the pre-clinical findings was found to be associated with improved survival in patients with HPV-associated malignancies. Together, these findings provide a rationale for the combination of HPV vaccine, NHS-IL12, and Entinostat in the clinical setting for patients with HPV16-associated malignancies.
2025-05-07 | GSE295238 | GEO
Project description:Human papillomavirus (HPV) E6 and E7 oncoproteins are expressed at all stages of HPV-mediated carcinogenesis and are essential drivers of cancers caused by high-risk HPV. Some of the activities of HPV E6 and E7, such as their interactions with host cellular tumor suppressors, have been characterized extensively. There is less information about how high-risk HPV E6 and E7 alter cellular responses to cytokines that are present in HPV-infected tissues and are an important component of the tumor microenvironment. We used several models of HPV oncoprotein activity to assess how E6 and E7 alter the cellular response to the pro-inflammatory cytokine IL-1beta. Models of early-stage HPV infection (human keratinocytes expressing HPV16 E6 and E7) and models of established HPV-positive head and neck cancers (patient-derived xenografts, head and neck cancer cell lines) exhibited similar dysregulation of IL-1 pathway genes and suppressed responses to IL-1beta treatment. Such overlap in cell responses supports that changes induced by HPV E6 and E7 early in infection could persist and contribute to a dysregulated immune environment throughout carcinogenesis. HPV E6 and E7 also drove the upregulation of several suppressors of IL-1 cytokine signaling, including SIGIRR, both in primary keratinocytes and in cancer cells. SIGIRR knockout was insufficient to increase IL-1beta-dependent gene expression in the presence of HPV16 E6 and E7, suggesting that multiple suppressors of IL-1 signaling contribute to dampened IL-1 responses in HPV16-positive cells.
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Project description:Human papilloma (HPV) virus-like particle (VLP) vaccines were recently licensed. Though neutralizing antibody titers are thought to be the main effectors of protection against infection, early predictors of long-term efficacy are not yet defined and a comprehensive understanding of innate and adaptive immune responses to vaccination is still lacking. Here, microarrays were used to compare the gene expression signature in HPV-16 L1 VLP-stimulated PBMC from 17 vaccine and 4 placebo recipients before vaccination, and 1 month after receiving the second immunization. Vaccination with HPV-16 L1 VLP was associated with modulation of genes involved in the inflammatory/defense response, cytokine, interferon and cell cycle pathways in VLP-stimulated PBMC. In addition, there was up-regulation of probesets associated with cytotoxic (GZMB, TNFSF10) and regulatory (INDO, CTLA4) activities. The strongest correlations with neutralizing antibody titers were found for cyclin d2 (CCND2) and galectin (LGALS2). Twenty-two differentially expressed probesets were selected for confirmation by RT-PCR in an independent sample set. Agreement with the microarray data was seen for over two-thirds of these probesets. Up-regulation of immune/defense response genes by VLP, in particular interferon-induced genes was observed in PBMC collected prior to vaccination, with many of these genes being further induced following vaccination. In conclusion, we used gene expression profiling to identify important innate and adaptive response related- genes induced by vaccination with HPV VLP. Further studies are needed to identify gene expression signatures of immunogenicity and long-term protection with potential utility in prediction of long-term HPV vaccination outcomes in clinical trials. Keywords: Time course - pre and post HPV immunizaton
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Project description:A research project is currently being undertaken looking at Human Papilloma Virus (HPV) vaccination in special risk groups. It aims to see if young women with a chronic illness respond well to the HPV vaccine or whether they may require additional doses to ensure protective immunity. The four valent HPV vaccine protects against HPV types 16 & 18, cervical cancer and HPV types 6 & 11, anogenital warts.
The six special risk groups include:
Paediatric Rheumatological Disease Inflammatory Bowel Disease Acute Lymphoblastic Leukaemia Solid Organ Transplant Recipients (kidney and liver) Chronic Renal Disease Bone Marrow Transplants This immunity is measured by antibody levels of the HPV types, which requires a single blood test one month after the final dose of HPV vaccine.
This is compared to healthy controls using antibody response to HPV vaccine. This will assess directly whether these special risk groups respond as well to the HPV vaccine.
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Project description:Successful development of HIV-vaccination strategies will also depend on the ability to use novel approaches to analyse and integrate immunogenicity data generated in vaccine trials. The ANRS VAC 18 trial evaluated the immunogenicity of HIV-LIPO-5 vaccine (5 HIV peptides coupled to a palmytoil tail) administered at W0, 4, 12 and 24 in healthy volunteers. 62-69% of vaccinees developed HIV-specific ELISpot responses by W26. Here we present extensive immunogenicity assessments in a subset of vaccinees using ELISpot, lymphoproliferation, intracellular cytokine staining (ICS), cytokine multiplex and transcriptomic analyses. Peripheral blood mononuclear cells from volunteers collected before and following vaccinations were stimulated with HIV LIPO 5 vaccine, Gag peptides contained or not in the vaccine as controls. Different time points and stimulation conditions were compared, using false discovery rate to control for test multiplicity. 74% and 30% of vaccinees had cultured ELISpot and lymphoproliferation responses at W14, respectively. Ex-vivo ICS showed mainly single IL-2 producing cells. Secretion of IFN-γ, TNF-α, IL-5, and IL-13 increased significantly in response to Gag stimulation after culture at W14 compared to W0. An induction of metallothionein genes was consistently detected after HIV-LIPO-5 stimulation at W0 and W14 related to the adjuvant effect of the lipid tail. After vaccination (W14), significant probes increased substantially (>1200 probes) including IFN-γ, CXCL9, IL2RA, TNFAIP6, CCL3L1 and IL-6 W14 (fold change > 100%). In conclusion, HIV LIPO-5 vaccination elicited memory precursor responses with a Th1 and Th2 profile. The signature profile before vaccination provides information about the adjuvant effect of the lipid tail. Consistently with cytokine responses, vaccination is associated with a modulation in gene expression. This combined approach allowed to identify new signatures of HIV vaccine response and indicates that HIV-LIPO-5 could be further developed as a prime component of heterologous prime boost strategies. PBMC mRNA of 12 healthy volunteers, stimulate in four different conditions (HIV-LIPO-5, Gag+, Gag-, NS) during 6 and 24 hours before and after vaccination (week 0 and week 14)
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