IL-6 signaling in CD8 T cells promotes resistance to anti-PD-L1 immunotherapy
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ABSTRACT:
PROVIDER: PRJNA818179 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11844363.fastq.gz | Fastqsanger.gz | |||
| SRR11844364.fastq.gz | Fastqsanger.gz | |||
| SRR11844365.fastq.gz | Fastqsanger.gz | |||
| SRR11844366.fastq.gz | Fastqsanger.gz | |||
| SRR11844367.fastq.gz | Fastqsanger.gz |
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Project description:Background & Aims: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastasis is reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Here, we aimed to investigate the role of IL-10 in liver metastasis formation and decipher its therapeutic potential in affecting immunotherapy effectiveness. Methods: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell-type specific deletion of IL-10- and IL-10Ra were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of IL-10 on PD-L1. Results: We found that Il10-deficient mice and mice treated with IL-10Ra antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e., monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions. Conclusions: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer (CRC)-derived liver metastasis. These findings provide the basis for future monitoring and targeting of IL-10 in CRC-derived liver metastasis.
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Project description:Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be an unfavorable prognostic factor in ovarian cancer. The purpose of this study was to elucidate the function of PD-L1 in peritoneal dissemination. Tumor cell lysis by CTLs was attenuated when PD-L1 on tumor cells was overexpressed and promoted when it was silenced. PD-L1 overexpression also inhibited gathering and degranulation of CTLs. Gene expression profile of mouse CTLs caused by PD-L1-overexpressing ovarian cancer was related to human CTLs exhaustion. In mouse ovarian cancer dissemination models, depleting PD-L1 expression on tumor cells resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival. Restoring immune function by inhibiting immune-suppressive factors such as PD-L1 may be a promising therapeutic strategy for peritoneal dissemination. Genome-wide transcriptional changes in OT-1 mouse CD8+ T cells that were co-incubated with OVA peptide-loaded ID8 mouse ovarian cancer cell lines. CTLs from 4 mice were devided into 2 groups, and co-incubated with PD-L1-overexpressed ID8 or PD-L1-depleted ID8.
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Project description:The ability to modulate immune-inhibitory pathways using checkpoint blockade antibodies such as PD-1, PD-L1, and CTLA-4 represents a significant breakthrough in cancer therapy in recent years. This has driven interest in identifying small-molecule-immunotherapy combinations to increase the proportion of responses. Murine syngeneic models, which have a functional immune system, represent an essential tool for pre-clinical evaluation of new immunotherapies. However, immune response varies widely between models and the translational relevance of each model is not fully understood, making selection of an appropriate pre-clinical model for drug target validation challenging. Utilizing RNAseq transcriptomic profiling, we have characterised the changes in gene regulatory pathways and immune populations in CT26 mice after treatment with the combination of anti-PD-L1 and anti-CTLA-4 antibodies. At day 7 post tumor implant, the pathways analysis of differentially expressed genes indicated an enrichment for migration of leukocytes in response to inflammation and communication between innate and adaptive immune cells. Similarly, analysis of upstream regulators suggested that lipopolysaccharide, IL-1B, TNF, IFNG, and NFKB1A pathways associated with inflammation were activated. At day 14, pathways related T-helper cell signalling pathways were upregulated. In addition, upstream regulators of the lipopolysaccharide and IFNG pathway, as well STAT1 and IL21 pathway were enriched, indicative of innate and adaptive immune response to inflammation.
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Project description:Targeting checkpoint blockade to rescue exhausted regulatory T cells (Tregs) has become an essential immunotherapy strategy in treating cancer. Until now, the CD4+ Tregs and PD-1+CD8+ T cells were demonstrated to reduce immunogenic responses. In contrast, little is known about the PD-L1 graphic pattern and characteristics in CD8+ T cells. We performed two high-throughput analysis approaches on tumor-infiltrating CD8+ T cells in lung cancers. We discovered PD-L1+CD8+ T cells enriched in tumor lesions, localized with PD-1+CD8+ affected T cells, and owned regulatory functions. Moreover, tumor-derived IL-27 promoted the development of PD-L1+CD8+ T cells through STAT1/STAT3 signaling. Single-cell RNA sequencing data analysis further clarified the enrichment of PD-L1+CD8+ T cells related to the downregulation of adaptive immune response. Additionally, enrichment of this subset was correlated with poor survival of lung cancer patients. Our data collectively demonstrated that PD-L1+CD8+ T cells potentially become a prognostic biomarker in lung cancer.
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