Immunotherapy: two populations of T cell precursors discovered in non-small cell lung cancer

The immune system doesn’t just protect us from infections, but also against cancer. This is the principle on which immunotherapy for cancer treatment is based. The leading cause of cancer related death throughout the world is lung cancer and 85% of such tumors are of the non-small cell lung cancer (NSCLC) subtype. The level of tumor infiltrating lymphoyctes (TILs) in NSCLC is known to confer favorable prognosis for patient survival. As TILs respond to tumors however they lose their effectiveness, a process which can be reprogrammed by certain checkpoint inhibitors in the clinic. The precise cellular and molecular mechanisms of this process are not very well understood. At Institut Curie, the “Immune responses and cancer” (Inserm, PSL Université, Université de Paris) team led by Sebastian Amigorena and the “Integrative Functional Genomics of Cancer” (Institut Curie, Inserm, PSL Université) team led by Josh Waterfall, succeeded in identifying two separate populations of precursors.

Thanks to cooperation from the team of Prof. Nicolas Girard, oncologist and pulmonologist heading the Curie-Montsouris Chest Center, the team was able to work on clinical samples.

These tumors come straight from the operating room. We work on them within just a few hours

explains Sebastian Amigorena. Interactions are structured by the Cancer Immunotherapy Center at Institut Curie.

To analyze the samples, the team used transcriptomic and single-cell technologies. “We take thousands of cells, which we separate one by one, and we identify all the RNA that they express. We combined that with a very recent technology to also identify the T cell receptor (TCR) in each cell. This receptor is how T cells recognize individual antigens on target cells.” The results obtained in 11 patients were integrated, with expression profiling on one side to understand the cellular state of each cell, and the TCR on the other to study antigen specificity.

A common core but two types of populations

The result: two populations of T cell precursors were identified that both contribute to the pool of TILs. One of these populations comes from circulating blood, and the other from the adjacent tissues

 explains Josh Waterfall.

“To begin with, these two populations are distinct.  However, once they enter the tumor, these populations converge through a similar transitionary process to become fully differentiated cells in terminal phase, which we say is dysfunctional, or exhausted. The population then becomes inactive and loses its ability to reject the tumor.”

“The data strongly suggest that the final stages in this differentiation process are associated with direct stimulation of the T cells by recognizing their antigen in the tumor” thanks to their specific receptors, Josh Waterfall explains. By identifying their target directly, the T cells finish differentiating.  Initially this leads to an immune reaction against the cancer cell. In the long term, however, this chronic stimulation makes them unable to effectively fight the tumor and this is what makes the T cell lymphocytes inactive.

These results provide a working model to better understand the origin of the lymphocytes infiltrating the tumors, their developmental trajectories and the functional organization in primary non-small cell lung cancer. For the moment, it is difficult to convert this work directly into therapeutic projects. But in the longer term, it could be used to define better biomarkers in order to predict which patients will respond well to immunotherapy. It could also be used to identify other therapeutic targets to be blocked, alone or in combination with others.

Reference: Contribution of resident and circulating precursors to tumor-infiltrating CD8+ T cell populations in non-small cell lung cancer patients. Paul Gueguen, Christina Metoikidou, Thomas Dupic, Myriam Lawand, Christel Goudot, Sylvain Baulande, Sonia Lameiras, Olivier Lantz, Nicolas Girard, Agathe Seguin-Givelet, Marine Lefevre, Thierry Mora, Aleksandra M. Walczak, Joshua J Waterfall, Sebastian Amigorena. Science Immunology. January 29, 2021.
doi: 10.1126/sciimmunol.abd5778

This work was funded by the Janssen Horizon Foundation, the ARC Cancer Research Foundation, the Chercher et Trouver Foundation, the European Research Council, the ANR and the Curie SIRIC program.