Frédéric Lagarrigue is laureate of the ATIP-Avenir funding program 2020 to develop his research on novel approaches to target macrophage integrins in cancer and inflammatory diseases at IPBS-Toulouse.
Infiltration of macrophages correlates with poor prognosis of solid malignancies. They enhance tumor growth and dissemination. Not surprisingly, therapies that aim to either deplete or reprogram macrophages merit considerable attention. However, caution has to be taken when modulating the immune responses as not to interfere with essential macrophage functions to maintain tissue homeostasis and immune surveillance. Remarkably, macrophages are capable of using the mesenchymal migratory mode, which requires integrin−mediated cell adhesion, to infiltrate dense tumors. In contrast, integrins are dispensable for leukocyte migration in healthy or inflamed tissues. This distinctive feature deserves attention for the purpose of specifically limiting the recruitment of macrophages in tumors to neutralize their roles on disease progression, while preserving beneficial macrophage functions. Integrin adhesion receptors are proven therapeutic targets in many diseases; however, complete blockade of their function by interfering with ligand binding often leads to mechanism-based toxicity limiting the use of integrin antagonists. Instead, F. Lagarrigue's project intends to target intracellular signaling pathways that orchestrate integrin functions in macrophages. This underestimated strategy aligns with the emerging paradigm that signaling events in leukocytes operate in both a cell-type and integrin-specific manner, thereby providing unique avenues to manipulate recruitment of particular leukocytes into specific tissues. Elegant in vivo models with either knockout or knock-in mutations in the key regulators of integrin function will be instrumental to decipher the signaling events that orchestrate integrin-dependent migration of macrophages. Meanwhile, the project will evaluate the potential of targeting these signaling pathways as novel avenues to manipulate macrophage tissue infiltration and recruitment into tumors. It will also identify new targets of integrin function with the potential of being more specific and more selective of macrophages, in particular tumor-associated macrophages. These studies endeavor to devise novel strategies for blockade of macrophage migration infiltration in tumors to synergize with combination therapies that simultaneously neutralize both protumoral stromal cells and cancer cells. Tissue densification is a common feature of chronic inflammatory disorders; hence this project could have far-reaching implications in other diseases involving macrophages.
Frédéric Lagarrigue is a research associate at the CNRS and is also supported by the Toulouse Cancer Santé Foundation and the Fondation de France.