The results of the MOTM project have been published in an open-access article in the journal Nature Communications (doi: 10.1038/s41467-024-46377-7). Here summary of the results obtained:
-) we have identified the metabolic requirements of human T cells migrating in a 3D environment, with a special focus on the tumor microenvironment. Specifically, T cell 3D motility is supported by TCA cycle fueled by glucose and glutamine but not fatty acids (Figure 1 of the Nat Commun paper).
-) we demonstrated the relative minor role played by glycolysis compared with mitochondrial OXPHOS in supporting human T cell 3D motility (Figure 2 of the Nat Commun paper).
-) we showed that human T cell 3D motility and mitochondrial metabolism are positively correlated in different contexts both at intra- and inter-population levels, including CD8+ T cells infiltrating non-small cell lung cancer (Figure 3 of the Nat Commun paper).
-) mechanistically, we identified both mitochondrial ATP and mitochondria-derived ROS (especially those produced by ETC complex II) as critical molecules produced by mitochondrial metabolism to sustain positively human T cell 3D migration (Figure 4 of the Nat Commun paper).
-) we have identified different strategies able to improve T cell 3D motility through a metabolic reprogramming (Figure 5 and Figure 8 of the Nat Commun paper). Among them, we further showed that treatment with rapamycin improves not only human T cell motility within a tumor microenvironment (Figure 6 of the Nat Commun paper) but also the infiltration of human CAR T cells into two preclinical xenograft human lung tumor models implanted in mice (Figure 7 of the Nat Commun paper), thus improving tumor control.
Overall, we have defined for the first time the metabolic requirements of T cells migrating within a solid tumor mass and we showed how metabolism in the tumor microenvironment may influence the motility of tumor-infiltrating T cells. Our study advances the field by providing two major advances:
-) First, by showing how mitochondrial metabolism supports the ability of T cells to migrate and infiltrate tumor islets, we provide an additional explanation for understanding the efficacy of antitumor strategies targeting mitochondria in T cells beyond the well-established effect on T cell persistence (which is the only explanation currently proposed in the field).
-) Second, from a clinical perspective, we have developed a simple in vitro pharmacological approach that allows the generation of CAR T cells with improved ability to infiltrate human solid tumors and with strong translational potential since it could be easily implemented in current CAR T cell production protocols. To our knowledge, this is the first immunometabolism approach against solid cancers focused on improving intratumoral CAR T cell motility.
These results of the project will be used by the MSCA fellow to apply for new research grants in the next years in order to continue the research on the topic of cancer immunotherapy and further extend the impact of the project for biomedical application in the immunotherapy field. The scientific impact of the MOTM action has been fully achieved, as the main questions posed in the project have been answered. No direct application in economic, societal, or industrial production or processes fields is envisaged now. However, the results of the MOTM action represent the basis for further scientific research that may lead to the setup of new immunotherapy approaches to fight against solid cancer and, therefore, may have an impact at industrial and well-being fields in the mid-term future. In line with this discussion is ongoing with clinicians at host institute Hospital center (Cochin) to implement the application of the identified strategies in clinical trials.
