Targeting PILRα, an immune checkpoint mediating T cell suppression, for cancer immunotherapy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1068114 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27700053_1.fastq.gz | Fastqsanger.gz | |||
| SRR27700053_2.fastq.gz | Fastqsanger.gz | |||
| SRR27700054_1.fastq.gz | Fastqsanger.gz | |||
| SRR27700054_2.fastq.gz | Fastqsanger.gz | |||
| SRR27700055_1.fastq.gz | Fastqsanger.gz |
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Project description:One of the most successful therapies in cancer treatment involves immune checkpoint blockade using the anti-programmed death-1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) antibody, which targets the interaction between tumors and T cells. However, the overall response rate is < 30% in patients with cancer. Therefore, there is an urgent need to identify additional immune checkpoints that can modulate T-cell function. In this study, we identified the tumor cell-expressed paired Ig-like type 2 receptor α (PILRα) as an immune suppressor that targets T cells, using a high-throughput screening approach. PILRα suppresses T-cell activation, proliferation, and effector function in both cultured cells and mouse xenograft and allograft models. It specifically targets CD99, a T cell surface antigen, to suppress the ZAP70/NFAT/IL2/JAK/STAT signaling in T cells. The cluster of O-glycosylated serine (Ser)/threonine (Thr) residues within the stalk region plays a critical role in PILRα–CD99 interactions, thereby influencing the immunosuppressive function of PILRα. Blocking interactions between PILRα and CD99 using an anti-PILRα antibody that targets the stalk region potently enhances T cell antitumor immunity and suppresses tumor growth. Additionally, when combined anti-PILRα with anti-PD-1 antibodies, synergistic effects on tumor suppression were observed. Notably, PILRα is highly expressed in various human cancers, and its expression levels serve as a predictive marker for poor prognosis in patients with cancer. Taken together, our results unveil PILRα as an immune checkpoint and highlight the promising therapeutic potential of targeting PILRα in clinical cancer immunotherapy.
2025-02-22 | GSE254013 | GEO
Project description:One of the most successful therapies in cancer treatment involves immune checkpoint blockade using the anti-programmed death-1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) antibody, which targets the interaction between tumors and T cells. However, the overall response rate is < 30% in patients with cancer. Therefore, there is an urgent need to identify additional immune checkpoints that can modulate T-cell function. In this study, we identified the tumor cell-expressed paired Ig-like type 2 receptor α (PILRα) as an immune suppressor that targets T cells, using a high-throughput screening approach. PILRα suppresses T-cell activation, proliferation, and effector function in both cultured cells and mouse xenograft and allograft models. It specifically targets CD99, a T cell surface antigen, to suppress the ZAP70/NFAT/IL2/JAK/STAT signaling in T cells. The cluster of O-glycosylated serine (Ser)/threonine (Thr) residues within the stalk region plays a critical role in PILRα–CD99 interactions, thereby influencing the immunosuppressive function of PILRα. Blocking interactions between PILRα and CD99 using an anti-PILRα antibody that targets the stalk region potently enhances T cell antitumor immunity and suppresses tumor growth. Additionally, when combined anti-PILRα with anti-PD-1 antibodies, synergistic effects on tumor suppression were observed. Notably, PILRα is highly expressed in various human cancers, and its expression levels serve as a predictive marker for poor prognosis in patients with cancer. Taken together, our results unveil PILRα as an immune checkpoint and highlight the promising therapeutic potential of targeting PILRα in clinical cancer immunotherapy.
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Project description:Single-agent immunotherapy has achieved limited clinical benefit to date in patients with pancreatic ductal adenocarcinoma (PDAC). This may be a result of the presence of a uniquely immunosuppressive tumor microenvironment (TME). Critical obstacles to immunotherapy in PDAC tumors include a high number of tumor-associated immunosuppressive cells and a uniquely desmoplastic stroma that functions as a barrier to T cell infiltration. We identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as an important regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlated with high levels of fibrosis and poor CD8+ cytotoxic T cell infiltration. Single-agent FAK inhibition using the selective FAK inhibitor VS-4718 substantially limited tumor progression, resulting in a doubling of survival in the p48-Cre;LSL-KrasG12D;Trp53flox/+ (KPC) mouse model of human PDAC. This delay in tumor progression was associated with markedly reduced tumor fibrosis and decreased numbers of tumor-infiltrating immunosuppressive cells. We also found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to T cell immunotherapy and PD-1 antagonists. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and renders tumors responsive to immunotherapy.
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