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GEO help: Mouse over screen elements for information. |
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Status |
Public on Feb 04, 2022 |
Title |
Programme of Self-Reactivity for Innate-Like T Cell-Mediated Cancer Immunosurveillance |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
The concept of cancer immunosurveillance ascribes a role of cellular immunity in eliminating transformed cells with cytotoxic CD8+ T cells being a primary mediator. Cancer cells can express neoantigens to prime conventional CD8+ T cells which nonetheless transition to a dysfunctional state of exhaustion characterized by high expression of the immune checkpoint co-inhibitory receptor PD-1. Despite the clinical success of anti-PD-1 to revive cancer immunity, many patients do not respond to checkpoint blockade therapies. Of note, recent studies have revealed an incredible heterogeneity among tumor-infiltrating CD8+ T cells with the PD-1+ population being only a fraction, and yet, beside the PD-1+ subset, the identity of other populations of CD8+ T cells remains largely unknown. Here, in an unbiased survey of CD8+ T cells present in murine and human malignancies, we rediscovered a population of FCER1G+ innate-like T cells that we have previously shown to possess high cytotoxic potential and are resistant to exhaustion, hereon termed ‘killer innate-like T cells’, or ILTCks. While tumor-infiltrating CD8+PD-1+ T cells were oligoclonal, ILTCks were polyclonal with broad reactivity to unmutated tumor-associated antigens. ILTCks were not differentiated from conventional CD8+ T cells, but arose from ILTCk-committed progenitors following early encounter with cognate antigens during thymocyte development. Committed ILTCk thymic progenitors were continuously generated throughout life, and replenished the ILTCk compartment during tumor progression. Notably, expansion and effector differentiation of intratumoral ILTCks depended on high expression of IL-15 in cancer cells, and inducible activation of IL-15 signaling in adoptively transferred ILTCk progenitors suppressed tumor growth. Thus, antigen receptor self-reactivity and unconventional ontogeny distinguish ILTCks from CD8+PD-1+ T cells as a new class of tumor-elicited immune response. Strategies targeting ILTCks may enhance and complement current conventional CD8+ T cell-based cancer immunotherapies, in particular against tumors with low mutation burden or refractory to checkpoint blockade modalities.
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Overall design |
Single-cell and bulk RNA-seq data corresponding to Chou,Zhang et al 2022. Single cell RNA-seq datasets include data from two cancer types- murine breast cancer (1 dataset in main figure, and 1 in extended), and two biological replicates of murine prostate cancer (TRAMP mice), for analysis in the extended figure. These datasets were generated to discover the abILTCk population. Bulk RNA-seq datasets correspond to thymic conventional CD8 single positive (SP) progenitors (2 biological replicates) and ILTCk progenitors (2 biological replicates) with analysis included in the extended figure, as well as murine NK1.1+/- abILTCk (2 biological replicates each) cells and PD1+ conventional T cells (2 biological replicates).
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Contributor(s) |
Krishna C, Leslie CS, Li MO, Chou C, Zhang X |
Citation(s) |
35444279 |
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Submission date |
Feb 01, 2022 |
Last update date |
Jul 14, 2022 |
Contact name |
Christina Leslie |
Organization name |
Memorial Sloan Kettering Cancer Center
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Street address |
1275 York Ave
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City |
New York |
ZIP/Postal code |
10065 |
Country |
USA |
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Platforms (1) |
GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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Samples (14)
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GSM5856679 |
scRNA data for mouse breast dataset in Fig. 1 |
GSM5856680 |
scRNA data for mouse breast dataset in Ext. Fig |
GSM5856681 |
scRNA data for mouse prostate rep1 dataset in Ext. Fig |
GSM5856682 |
scRNA data for mouse prostate rep2 dataset in Ext. Fig |
GSM5856683 |
bulk RNA data for CD8SP rep1 dataset in Ext. Fig |
GSM5856684 |
bulk RNA data for CD8SP rep2 dataset in Ext. Fig |
GSM5856685 |
bulk RNA data for ILTCkP rep1 dataset in Ext. Fig |
GSM5856686 |
bulk RNA data for ILTCkP rep2 dataset in Ext. Fig |
GSM5856687 |
bulk RNA data for NK1.1- ILTCk rep1 dataset in Ext. Fig |
GSM5856688 |
bulk RNA data for NK1.1- ILTCk rep2 dataset in Ext. Fig |
GSM5856689 |
bulk RNA data for NK1.1+ ILTCk rep1 dataset in Ext. Fig |
GSM5856690 |
bulk RNA data for NK1.1+ ILTCk rep2 dataset in Ext. Fig |
GSM5856691 |
bulk RNA data for PD1+ Tconv rep1 dataset in Ext. Fig |
GSM5856692 |
bulk RNA data for PD1+ Tconv rep2 dataset in Ext. Fig |
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Relations |
BioProject |
PRJNA802670 |
Supplementary file |
Size |
Download |
File type/resource |
GSE195937_CD8SP_ILTCkP_counts.csv.gz |
348.8 Kb |
(ftp)(http) |
CSV |
GSE195937_Mouse_breast_ExtFig_scRNA_SeuratObj.rds.gz |
178.0 Mb |
(ftp)(http) |
RDS |
GSE195937_Mouse_breast_Fig1_scRNA_SeuratObj.rds.gz |
82.4 Mb |
(ftp)(http) |
RDS |
GSE195937_Mouse_prostate_ExtFig_scRNA_SeuratObj.rds.gz |
1.2 Gb |
(ftp)(http) |
RDS |
GSE195937_NK1.1neg_NK1.1pos_PD1posTconv_counts.csv.gz |
453.0 Kb |
(ftp)(http) |
CSV |
SRA Run Selector |
Raw data are available in SRA |
Processed data are available on Series record |
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