| First Author | Torres-Mejia E | Year | 2025 |
| Journal | Cancer Immunol Res | Volume | 13 |
| Issue | 4 | Pages | 496-516 |
| PubMed ID | 39745382 | Mgi Jnum | J:385705 |
| Mgi Id | MGI:8343306 | Doi | 10.1158/2326-6066.CIR-24-0184 |
| Citation | Torres-Mejia E, et al. (2025) Lung Cancer-Intrinsic SOX2 Expression Mediates Resistance to Checkpoint Blockade Therapy by Inducing Treg-Dependent CD8+ T-cell Exclusion. Cancer Immunol Res 13(4):496-516 |
| abstractText | Tumor cell-intrinsic signaling pathways can drastically affect the tumor immune microenvironment, promoting tumor progression and resistance to immunotherapy by excluding immune cell populations from the tumor. Several tumor cell-intrinsic pathways have been reported to modulate myeloid-cell and T-cell infiltration, creating "cold" tumors. However, clinical evidence suggests that excluding cytotoxic T cells from the tumor core also mediates immune evasion. In this study, we find that tumor cell-intrinsic SOX2 signaling in non-small cell lung cancer induces the exclusion of cytotoxic T cells from the tumor core and promotes resistance to checkpoint blockade therapy. Mechanistically, tumor cell-intrinsic SOX2 expression upregulates CCL2 in tumor cells, resulting in increased recruitment of regulatory T cells (Treg). CD8+ T-cell exclusion depended on Treg-mediated suppression of tumor vasculature. Depleting tumor-infiltrating Tregs via glucocorticoid-induced TNF receptor-related protein restored CD8+ T-cell infiltration and, when combined with checkpoint blockade therapy, reduced tumor growth. These results show that tumor cell-intrinsic SOX2 expression in lung cancer serves as a mechanism of immunotherapy resistance and provide evidence to support future studies investigating whether patients with non-small cell lung cancer with SOX2-dependent CD8+ T-cell exclusion would benefit from the depletion of glucocorticoid-induced TNFR-related protein-positive Tregs. |
