Abstract EN:

Tumor cells express antigens recognized by T cells and are thus able to trigger an anti-tumor adaptive immune response. However, these responses often turn out to be mostly ineffective. The tumor immunosuppressive environment is often pointed to account for such failures of T cell anti-tumor functions. My PhD work emphasizes another explanatory factor, commonly overlooked, which is T cell distribution within tumors. In most carcinomas, T cells are indeed preferentially found in the peri-tumoral stroma rather than in tumor nests. As tumor cells are considered as their main targets, the uneven distribution of T cells within tumors could restrict their anti-tumor functions and represent a major obstacle to T cell-based immunotherapy. My PhD project consisted in studying elements that control T cell distribution and migration within solid tumors. To that end, we used a real-time imaging approach to visualize recruitment and mobility of fluorescent T cells in viable slices of human lung tumors. Slices were made from fresh tumor biopsies of lung cancer patients and from a xenograft model of human tumors developed in immunodeficient mice. Overlaid T cells behave like their endogenous counterparts and preferentially migrate into the stroma. Our results reveal that matrix fibers organization plays a key role in controlling T cell positioning and migration within tumors. Active T cell motility, partly dependent on chemokines, is observed in loose fibronectin regions, whereas T cells poorly migrate in dense matrix areas. Besides, parallel fibers around tumor epithelial cell region dictate the migratory trajectory of T cells and restrict them from entering tumor islets. In conclusion, our results shed light on the importance of stromal matrix fibers which regulate anti-tumor immunity by controlling T cell infiltration into tumor nests.