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Project

How high endothelial venules support anti-tumoral immunity in cancer

Cancer immunotherapy has revolutionized the field of oncology and substantially extended the life of cancer patients. However, only a subset of patients has responded to immunotherapy. One of the major obstacles in immunotherapy is the scarce infiltration and the dysfunctional status of immune effector cells in malignant lesions. Conversely, the formation of tumor-associated tertiary-lymphoid structures (TU-TLS), typically composed of high endothelial venules (HEV) and lymphoid aggregates, is associated with a good prognosis in many cancer patients. However, how these structures develop remains poorly understood. By using several technologies including single-cell RNA-sequencing (scRNA-seq), endothelial fate mapping, genetic mouse models, high-parameter flow cytometry, and multiplex immunohistochemistry, we discovered that:

- Tumoral HEVs (TU-HEV) display a hybrid phenotype of tumor endothelial cells (TU-EC) and lymph node HEVs (LN-HEV) with a prominent IFNg gene expression signature.

- Antiangiogenic immunotherapies induce the transition of postcapillary venules into inflamed TU-HEVs. TU-HEVs predominantly generate lymphocyte niches resembling tertiary lymphoid-like structures (TLLS).

- HEV+ immune niches entail PD-1- and PD-1+TCF-1+TIM-3- progenitor (pTEX) CD8 T cells.

- pTEX cells expand preferentially around TU-HEVs and produce cytotoxic PD-1+TCF-1-TIM-3+ terminally differentiated (tTEX) CD8 T cells that may facilitate anti-tumoral immunity.

- TU-HEVs require CD8 and NK cell-derived lymphotoxin signals.

- A TU-HEV signature predicts and correlates with response to immune checkpoint blockade therapies in melanoma and non-small cell lung cancer (NSCLC).

Date:1 Feb 2018 →  16 Feb 2023
Keywords:cancer, metastases
Disciplines:Morphological sciences, Oncology
Project type:PhD project