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Targeting KRASG12V mutations with HLA class II restricted TCR for the immunotherapy in solid tumors

ABSTRACT: Targeting KRASG12V mutations with HLA class II restricted TCR for the immunotherapy in solid tumors

PROVIDER: PRJNA974393 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24658663_1.fastq.gz	Fastqsanger.gz
	SRR24658663_2.fastq.gz	Fastqsanger.gz
	SRR24658664_1.fastq.gz	Fastqsanger.gz
	SRR24658664_2.fastq.gz	Fastqsanger.gz
	SRR24658665_1.fastq.gz	Fastqsanger.gz

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Targeting KRASG12V mutations with HLA class II restricted TCR for the immunotherapy in solid tumors

Project description:To investigate the sequences of TILs, the sorted T cells were used for the following TCR sequencing analysis by 10X genomics Single Cell Sequencing. For the quality inspection and counting of single cell suspension, the cell survival rate is generally required to be more than 80%.

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Mtb HLA-E tetramer sorted CD8+ T-cells have a diverse TCR repertoire

Project description:HLA-E molecules can present self and pathogen-derived peptides to both NK-cells and T-cells. T-cells that recognize HLA-E peptides via their T-cell receptor (TCR) are termed donor-unrestricted T-cells due to restricted allelic variation of HLA-E. The composition and repertoire of HLA-E TCRs is not known so far. We performed TCR sequencing on CD8+ T-cells from 21 individuals recognizing HLA-E tetramers (TM) folded with 2 Mtb HLA-E restricted peptides. We sorted HLA-E Mtb TM+ and TMCD8+ T-cells directly ex vivo and performed bulk RNA-sequencing and single cell TCR sequencing. The identified TCR repertoire was diverse and showed no conservation between and within individuals. TCRs selected from our single cell TCR sequencing data could be activated upon HLA-E/peptide stimulation, although not robust, reflecting potentially weak interactions between HLA-E peptide complexes and TCRs. Thus, HLA-E Mtb specific T-cells have a highly diverse TCR repertoire.

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Targeting KRAS<sup>G12V</sup> mutations with HLA class II-restricted TCR for the immunotherapy in solid tumors.

Project description:KRAS mutation is a significant driving factor of tumor, and KRASG12V mutation has the highest incidence in solid tumors such as pancreatic cancer and colorectal cancer. Thus, KRASG12V neoantigen-specific TCR-engineered T cells could be a promising cancer treatment approach for pancreatic cancer. Previous studies had reported that KRASG12V-reactive TCRs originated from patients' TILs could recognized KRASG12V neoantigen presented by specific HLA subtypes and remove tumor persistently in vitro and in vivo. However, TCR drugs are different from antibody drugs in that they are HLA-restricted. The different ethnic distribution of HLA greatly limits the applicability of TCR drugs in Chinese population. In this study, we have identified a KRASG12V-specific TCR which recognized classII MHC from a colorectal cancer patient. Interestingly, we observed that KRASG12V-specific TCR-engineered CD4+ T cells, not CD8+ T cells, demonstrated significant efficacy in vitro and in xenograft mouse model, exhibiting stable expression and targeting specificity of TCR when co-cultured with APCs presenting KRASG12V peptides. TCR-engineered CD4+ T cells were co-cultured with APCs loaded with neoantigen, and then HLA subtypes were identified by the secretion of IFN-γ. Collectively, our data suggest that TCR-engineered CD4+ T cells can be used to target KRASG12V mutation presented by HLA-DPB1*03:01 and DPB1*14:01, which provide a high population coverage and are more suitable for the clinical transformation for Chinese, and mediate tumor killing effect like CD8+ T cells. This TCR hold promise for precision therapy in immunotherapy of solid tumors as an attractive candidate.

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