NCBI Logo
GEO Logo
   NCBI > GEO > Accession DisplayHelp Not logged in | LoginHelp
GEO help: Mouse over screen elements for information.
          Go
Series GSE245436 Query DataSets for GSE245436
Status Public on Apr 24, 2024
Title The efficacy of LCMV-based cancer vaccines is unleashed by intratumoral injections of polyI:C
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary 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
 
Overall design TC1/A9 tumor-bearing mice received intravenous treatment with 1×105 RCV FFU artLCMV-E7E6 on day 7 and intratumoral injections of 50 μg of poly(I:C) in the right tumor lesion on days 7, 10, and 13. On day 8 and day 14, mice were euthanized, and RNA from tumors was subjected to RNAseq analysis.
 
Contributor(s) Gomar C, González-Gomariz J, Berraondo P
Citation(s) 38631714
Submission date Oct 16, 2023
Last update date Apr 24, 2024
Contact name Jose Gonzalez
E-mail(s) jgonzalezgom@unav.es
Organization name FIMA
Street address C/PIO XII s/n
City Pamplona
State/province Navarra
ZIP/Postal code 31008
Country Spain
 
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (36)
GSM7842737 Vehicle (PBS) control treated tumor biological replicate 1 DAY 1
GSM7842738 Vehicle (PBS) control treated tumor biological replicate 2 DAY1
GSM7842739 Vehicle (PBS) control treated tumor biological replicate 3 DAY1
Relations
BioProject PRJNA1028509

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE245436_RNAseq_log2cpm_day1_normalized_counts.txt.gz 2.5 Mb (ftp)(http) TXT
GSE245436_RNAseq_log2cpm_day7_normalized_counts.txt.gz 2.4 Mb (ftp)(http) TXT
SRA Run SelectorHelp
Raw data are available in SRA
| NLM | NIH | GEO Help | Disclaimer | Accessibility |
NCBI Home NCBI Search NCBI SiteMap