Session 2:  Microenvironment and resistance 

Tumor-associated myeloid cells: Harnessing integrins to disrupt their contribution to cancer progression

Integrins are a family of widely expressed cell adhesion receptors. They exert multifaceted roles involved in almost all steps of cancer progression, from primary tumor development to metastasis. But their complexity and sometimes antagonistic roles in cancer cells and the tumor microenvironment challenge their therapeutic targeting. However, they stand out as interesting targets to recalibrate immune responses in local microenvironments, as they are essential for immune cell trafficking, activation, and function. To this end, we have identified several intracellular signaling pathways that orchestrate integrin activities in immune cells and shown that although these pathways coexist, their relative contribution depends on the type of cell and the type of integrin. Here, we discuss how to exploit these modules to hijack the protumor role of myeloid cells, in complete rupture with the hitherto widely explored targeting of the extracellular domain of integrins that has proven disappointing. We focus primarily on macrophages, whose abundance correlates with poor prognosis in most solid cancers, and on osteoclasts that promote bone metastasis. We reveal that they use integrin regulatory pathways in a unique way, different from other immune cells, and propose that their interference could help to specifically target protumor cell subsets. Thus, our findings may pave the way to new and unexpected ways to break the vicious cycle between myeloid cells and cancer cells to synergize with combination therapies.