Circadian tumor infiltration and function of CD8+ T cells dictate a temporal response to immunotherapy
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ABSTRACT:
PROVIDER: PRJNA1082390 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28171379_1.fastq.gz | Fastqsanger.gz | |||
| SRR28171379_2.fastq.gz | Fastqsanger.gz | |||
| SRR28171380_1.fastq.gz | Fastqsanger.gz | |||
| SRR28171380_2.fastq.gz | Fastqsanger.gz | |||
| SRR28171381_1.fastq.gz | Fastqsanger.gz |
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Project description:The quantity and quality of tumor-infiltrating lymphocytes (TILs), particularly CD8+ T cells, are parameters linked to tumor control and response to immunotherapy. Yet, it is unknown whether these parameters are controlled in a circadian manner. Here, we show in murine and human cancers that the phenotype and number of TILs show time-of-day differences, which are driven by rhythmic leukocyte infiltration and depend on the circadian clock machinery. These rhythms can be harnessed therapeutically: chimeric antigen receptor (CAR) T cells or immune checkpoint blockers produce significant antitumor benefits when administered at the optimal time of the day, but have little effect when administered at other times. Furthermore, time-of-day-dependent T cell signatures in murine tumor models predict overall survival in melanoma patients and correlate with response to anti-PD-1 therapy. Our data provide unexpected evidence of circadian dynamics in the tumor microenvironment (TME), and suggest the importance of exploiting them in prospective clinical trials.
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Project description:The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation plays an essential role in host defense as well as tumor immunosurveillance. Using a single cell RNA-sequencing approach in a genetic model of colorectal cancer (CRC), we identified clock-dependent changes to the immune landscape that dictate the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8+ T cells. Of these immunosuppressive cell types, PD-L1 expressing myeloid-derived suppressor cells (MDSCs) peak in abundance in a rhythmic manner. Mechanistically, we identified that disruption of the epithelial cell clock regulates the secretion of cytokines and chemokines that promote heightened inflammation, recruitment of neutrophils, and the subsequent development of MDSCs. We leveraged these findings to demonstrate that time-of-day delivery of anti-PD-L1 immunotherapy is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, our results indicate that circadian gating of tumor immunosuppression informs the timing and optimal efficacy of immune checkpoint inhibitors (ICIs).
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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.
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