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Commensal Bifidobacterium Strains Enhance the Efficacy of Neo-Epitope Based Cancer Vaccines.

ABSTRACT: A large body of data both in animals and humans demonstrates that the gut microbiome plays a fundamental role in cancer immunity and in determining the efficacy of cancer immunotherapy. In this work, we have investigated whether and to what extent the gut microbiome can influence the antitumor activity of neo-epitope-based cancer vaccines in a BALB/c-CT26 cancer mouse model. Similarly to that observed in the C57BL/6-B16 model, Bifidobacterium administration per se has a beneficial effect on CT26 tumor inhibition. Furthermore, the combination of Bifidobacterium administration and vaccination resulted in a protection which was superior to vaccination alone and to Bifidobacterium administration alone, and correlated with an increase in the frequency of vaccine-specific T cells. The gut microbiome analysis by 16S rRNA gene sequencing and shotgun metagenomics showed that tumor challenge rapidly altered the microbiome population, with Muribaculaceae being enriched and Lachnospiraceae being reduced. Over time, the population of Muribaculaceae progressively reduced while the Lachnospiraceae population increased-a trend that appeared to be retarded by the oral administration of Bifidobacterium. Interestingly, in some Bacteroidales, Prevotella and Muribaculacee species we identified sequences highly homologous to immunogenic neo-epitopes of CT26 cells, supporting the possible role of "molecular mimicry" in anticancer immunity. Our data strengthen the importance of the microbiome in cancer immunity and suggests a microbiome-based strategy to potentiate neo-epitope-based cancer vaccines.

SUBMITTER: Tomasi M

PROVIDER: S-EPMC8619961 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Commensal <i>Bifidobacterium</i> Strains Enhance the Efficacy of Neo-Epitope Based Cancer Vaccines.

Tomasi Michele M Dalsass Mattia M Beghini Francesco F Zanella Ilaria I Caproni Elena E Fantappiè Laura L Gagliardi Assunta A Irene Carmela C König Enrico E Frattini Luca L Masetti Giulia G Isaac Samine Jessica SJ Armanini Federica F Cumbo Fabio F Blanco-Míguez Aitor A Grandi Alberto A Segata Nicola N Grandi Guido G

Vaccines 20211118 11

A large body of data both in animals and humans demonstrates that the gut microbiome plays a fundamental role in cancer immunity and in determining the efficacy of cancer immunotherapy. In this work, we have investigated whether and to what extent the gut microbiome can influence the antitumor activity of neo-epitope-based cancer vaccines in a BALB/c-CT26 cancer mouse model. Similarly to that observed in the C57BL/6-B16 model, <i>Bifidobacterium</i> administration per se has a beneficial effect ...[more]

PMID: 34835287

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Project description:BackgroundOverexpression of nonmutated proteins involved in oncogenesis is a mechanism by which such proteins become immunogenic. We questioned whether overexpressed colorectal cancer associated proteins found at higher incidence and associated with poor prognosis could be effective vaccine antigens. We explored whether vaccines targeting these proteins could inhibit the development of intestinal tumors in the azoxymethane (AOM)-induced colon model and APC Min mice.MethodsHumoral immunity was evaluated by ELISA. Web-based algorithms identified putative Class II binding epitopes of the antigens. Peptide and protein specific T-cells were identified from human peripheral blood mononuclear cells using IFN-gamma ELISPOT. Peptides highly homologous between mouse and man were formulated into vaccines and tested for immunogenicity in mice and in vivo tumor challenge. Mice treated with AOM and APC Min transgenic mice were vaccinated and monitored for tumors.ResultsSerum IgG for CDC25B, COX2, RCAS1, and FASCIN1 was significantly elevated in colorectal cancer patient sera compared to volunteers (CDC25B p=0.002, COX-2 p=0.001, FASCIN1 and RCAS1 p<0.0001). Epitopes predicted to bind to human class II MHC were identified for each protein and T-cells specific for both the peptides and corresponding recombinant protein were generated from human lymphocytes validating these proteins as human antigens. Some peptides were highly homologous between mouse and humans and after immunization, mice developed both peptide and protein specific IFN-γ-secreting cell responses to CDC25B, COX2 and RCAS1, but not FASCIN1. FVB/nJ mice immunized with CDC25B or COX2 peptides showed significant inhibition of growth of the syngeneic MC38 tumor compared to control (p<0.0001). RCAS1 peptide vaccination showed no anti-tumor effect. In the prophylactic setting, after immunization with CDC25B or COX2 peptides mice treated with AOM developed significantly fewer tumors as compared to controls (p<0.0002) with 50% of mice remaining tumor free in each antigen group. APC Min mice immunized with CDC25B or COX2 peptides developed fewer small bowel tumors as compared to controls (p=0.01 and p=0.02 respectively).ConclusionsImmunization with CDC25B and COX2 epitopes consistently suppressed tumor development in each model evaluated. These data lay the foundation for the development of multi-antigen vaccines for the treatment and prevention of colorectal cancer.

Project description:Background Lymphocytic choriomeningitis virus (LCMV) belongs to the Arenavirus family known for inducing strong cytotoxic T-cell responses in both mice and humans. LCMV has been engineered for the development of anti-tumor vaccines, currently undergoing evaluation in phase I/II clinical trials. Initial findings have demonstrated safety and an exceptional ability to induce and expand tumor-specific T lymphocytes. Combination strategies to maximize the anti-tumor effectiveness of LCMV-based vaccines are required. Methods We assessed the anti-tumor therapeutic effects of intratumoral administration of polyinosinic:polycytidylic acid (poly(I:C)) and systemic vaccination using an LCMV-vector expressing non-oncogenic versions of the E6 and E7 antigens of human papillomavirus 16 (artLCMV-E7E6) in a bilateral model engrafting TC-1/A9 cells. This cell line, derived from the parental TC-1, exhibits low MHC class I expression and is highly immune-resistant. The mechanisms underlying the combination's efficacy were investigated through bulk RNAseq, flow cytometry analyses of the tumor microenvironment, selective depletions using antibodies and clodronate liposomes, Batf3 deficient mice, and in vivo bioluminescence experiments. Finally, we assessed the anti-tumor effectiveness of the combining of LCMV-E6E7 with BO-112, a GMP-grade poly(I:C) formulated in polyethyleneimine, currently under evaluation in clinical trials. Results Intratumoral injection of poly(I:C) enhanced the anti-tumor efficacy of artLCMV-E7E6 in both injected and non-injected tumor lesions. The combined treatment resulted in a significant delay in tumor growth and often complete eradication of several tumor lesions, leading to significantly improved survival compared to monotherapies. While intratumoral administration of poly(I:C) did not impact LCMV vector biodistribution or transgene expression, it significantly modified leukocyte infiltrates within the tumor microenvironment and amplified systemic efficacy through proinflammatory cytokines/chemokines such as CCL3, CCL5, CXCL10, TNF, IFNα, and IL12p70. Upregulation of MHC on tumor cells and a reconfiguration of the gene expression programs related to tumor vasculature, leukocyte migration, and the activation profile of tumor-infiltrating CD8+ T lymphocytes were observed. Indeed, the anti-tumor effect relied on the functions of CD8+ T lymphocytes and macrophages. The synergistic efficacy of the combination was further confirmed when BO-112 was included. Conclusion Intratumoral injection of poly(I:C) sensitizes MHClow tumors to the anti-tumor effects of artLCMV-E7E6, resulting in a potent therapeutic synergy

Dataset Information

Commensal Bifidobacterium Strains Enhance the Efficacy of Neo-Epitope Based Cancer Vaccines.

Publications

Commensal <i>Bifidobacterium</i> Strains Enhance the Efficacy of Neo-Epitope Based Cancer Vaccines.

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