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Series GSE260743 Query DataSets for GSE260743
Status Public on Mar 04, 2024
Title Dendritic cell-targeted therapy expands CD8 T cell responses to bona-fide neoantigens in lung tumors
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Cross-presentation by type 1 DCs (cDC1) is critical to induce and sustain antitumoral CD8 T cell responses to model antigens, in various tumor settings. However, the impact of cross-presenting cDC1 and the potential of DC-based therapies in tumors carrying varied levels of bona-fide neoantigens (neoAgs) remains unclear. We develop a hypermutated model of non-small cell lung cancer, encoding genuine MHC-I neoepitopes to study neoAgs-specific CD8 T cell responses in spontaneous settings and upon Flt3L+CD40 (DC-therapy). We find that cDC1 are required to generate broad CD8 responses against a range of diverse neoAgs. DC-therapy promotes immunogenicity of weaker neoAgs and strongly inhibits the growth of high tumor-mutational burden (TMB) tumors. In contrast, low TMB tumors respond poorly to DC-therapy, generating mild CD8 T cell responses that are not sufficient to block progression. scRNA transcriptional analysis, immune profiling and functional assays unveil the changes induced by DC-therapy in lung tissues, which comprise accumulation of cDC1 with increased immunostimulatory properties and decreased exhaustion in effector CD8 T cells. We conclude that boosting cDC1 activity is critical to broaden the diversity of anti-tumoral CD8 T cell responses and to leverage neoAgs content for therapeutic advantage.
 
Overall design Briefly, KP cells were transiently transfected with pZac2.1-U6sgRNA-CMV-ZsGreen and (pSpCas9(BB)(PX458) using Lipofectamine 3000 (Invitrogen), following the manufacturer´s instructions. ZsGreen+ cells were cell sorted. Mlh1 knockout clones were generated by Crispr Cas9 based technology using 2 single guide RNAs (sgRNA) targeting Mlh1 exon 5 as described previuosly. and single clones were tested for Mlh1 expression. KPctrl cells derive from cells transiently transfected with only (pSpCas9(BB)(PX458). Then, RNA extraction was performed in triplicates using RNeasy Mini kit (Qiagen).
 
Contributor(s) Benvenuti F, López L, Piazza S, Rospo G, Amadio R, Germano G
Citation(s) 38480738
Submission date Mar 03, 2024
Last update date Mar 20, 2024
Contact name Silvano Piazza
E-mail(s) silvano.piazza@icgeb.org
Organization name ICGEB
Lab Computational Biology
Street address localita' Padriciano 99
City Trieste
ZIP/Postal code 34149
Country Italy
 
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (6)
GSM8123453 MLH1_CAS9_1
GSM8123454 MLH1_CAS9_2
GSM8123455 MLH1_CAS9_3
Relations
BioProject PRJNA1083206

Download family Format
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE260743_countdata.txt.gz 455.5 Kb (ftp)(http) TXT
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Raw data are available in SRA

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