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| Status |
Public on Jul 30, 2024 |
| Title |
Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8 T cells [dataset 1] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Other
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| Summary |
Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. We performed RNA+TCR single-cell analysis across time in 36 stage IV melanoma patients treated with anti-PD-1, anti-CTLA-4, or combination therapy. We developed the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induced waves of clonal T cell responses that peaked at distinct timepoints. Combination therapy resulted in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8 T cells and exhausted CD8 T cell (TEX) clones. Focused analyses of TEX identified that anti-CTLA-4 induced robust expansion and proliferation of progenitor TEX, which synergized with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.
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| Overall design |
We performed single-cell RNA+TCR+ADT sequencing on PBMCs collected from 32 melanoma patients at baseline and every 3 weeks after checkpoint blockade (aPD-1, aCTLA-4, or combination aPD-1+aCTLA-4).
The 'cd8_nn_labeled_FINAL.RDS' is a Seurat object which contains all the non-naive CD8 T cell single-cell data used for the associated manuscript.
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| Contributor(s) |
Wang K, Paulina C, Brocks D, Wang G, Azar T, Solis S, Nandi A, Anderson S, Han N, Manne S, Kiner E, Sachar C, Lucas M, George S, Yan PK, Kier MW, Laughlin AI, Kothari S, Giles J, Mathew D, Ghinnagow R, Alanio C, Flowers A, Xu W, Tenney DJ, Xu X, Amaravadi RK, Karakousis GC, Schuchter LM, Buggert M, Oldridge D, Minn A, Blank C, Weber JS, Mitchell TC, Farwell MD, Herati RS, Huang AC |
| Citation(s) |
39214097 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| K08 CA230157 |
Role of tumor burden in limiting durable reinvigoration by PD-1 blockade |
UNIVERSITY OF PENNSYLVANIA |
Alexander Huang |
| R01 CA273018 |
Role of progenitor exhausted CD8 T cells and the progenitor niche in anti-PD1 efficacy |
UNIVERSITY OF PENNSYLVANIA |
Alexander Huang |
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| BioProject |
PRJNA1138883 |
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| Submission date |
Jul 24, 2024 |
| Last update date |
Oct 08, 2024 |
| Contact name |
Alexander C Huang |
| E-mail(s) |
alexander.huang@pennmedicine.upenn.edu
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| Organization name |
University of Pennsylvania
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| Department |
Department of Hematology/Oncology
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| Street address |
421 Curie Boulevard
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| City |
Philadelphia |
| State/province |
PA |
| ZIP/Postal code |
19104 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (360)
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| Supplementary file |
Size |
Download |
File type/resource |
| GSE272993_RAW.tar |
13.0 Gb |
(http)(custom) |
TAR (of CSV, FASTA, MTX, TSV) |
| GSE272993_cd8_nn_labeled_FINAL.RDS.gz |
2.0 Gb |
(ftp)(http) |
RDS |
| GSE272993_feature_reference_PNL-1-plusIgG.csv.gz |
1.0 Kb |
(ftp)(http) |
CSV |
| GSE272993_feature_reference_PNL-1.csv.gz |
1009 b |
(ftp)(http) |
CSV |
| GSE272993_feature_reference_PNL-10.csv.gz |
1.0 Kb |
(ftp)(http) |
CSV |
| GSE272993_feature_reference_PNL-2.csv.gz |
1.5 Kb |
(ftp)(http) |
CSV |
| GSE272993_feature_reference_hash.csv.gz |
300 b |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
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