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| Status |
Public on Jan 22, 2023 |
| Title |
Human CD4 cytotoxic T lymphocytes mediate potent tumor control via tumor cell HLA 2 class II expression in a humanized immune system mouse model |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Efficacy of immune checkpoint inhibitors in cancer can be limited by dysfunction of CD8 T cells or down-regulation of HLA class I. Tumor control mechanisms independent of the CD8/HLA-I axis would bypass these limitations. CD4 cytotoxic T lymphocytes (CTLs) have been detected in diverse human cancers. However, their independent roles in tumor immunity are underexplored. Here, we report CD4 T cell-dependent spontaneous tumor regression and subsequent memory responses in a humanized immune system (HIS) mouse model. HT-29 tumors, which upregulate HLA class II expression in response to IFN-γ, regressed or were eliminated in a subset of tumor implanted HIS mice. Mice with regressing tumors showed increased cytotoxic CD4 T cells in blood and tumors and enhanced HLA-II expression on tumor cells compared to mice with progressing tumors. The intratumoral CD4 T cell subset associated with tumor regression expressed multiple cytotoxic markers and exhibited clonal expansion. Notably, tumor control was abrogated by depletion of CD4 but not CD8 T cells. CD4 T cells derived from tumor-regressing mice exhibited HLA-II-dependent and tumor cell-specific killing ex vivo. Taken together, our study demonstrates a critical role of human CD4 CTLs in mediating potent tumor control independent of CD8 T cells and provides a novel platform to study human CD4 CTL-mediated anti-tumor immunity.
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| Overall design |
Data includes untreated same donor-engrafted StRG47 HIS mice implanted with HT-29 colon tumor. Tumor samples were collected after 1 month and sorted human CD45+ and mouse CD45+ for sequencing. There are 11 samples in total, 5 StRG47 HIS regressors and 6 StRG47 HIS progressors. The single cell data is aligned to both the human and mouse genome and the TCR data is aligned to human.
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| Web link |
https://doi.org/10.1038/s42003-023-04812-3
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| Contributor(s) |
Lin W, Singh V, Springer R, Choonoo G, Gupta N, Khatri A, Frleta D, Zhong J, Owczarek T, Macdonald L, Murphy A, Thurston G, Mohrs M, Ioffe E, Lu Y |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Jan 17, 2023 |
| Last update date |
Apr 25, 2023 |
| Contact name |
Gabrielle Choonoo |
| Organization name |
Regeneron Pharmaceuticals, Inc
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| Street address |
777 Old Saw Mill River Rd
|
| City |
Tarrytown |
| State/province |
NY |
| ZIP/Postal code |
10591 |
| Country |
USA |
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| Platforms (2) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
| GPL25526 |
Illumina NovaSeq 6000 (Homo sapiens; Mus musculus) |
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| Samples (22)
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| Relations |
| BioProject |
PRJNA924727 |
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