Abstract
Myeloid cells are recruited to damaged tissues where they can resolve infections and tumor growth or stimulate wound healing and tumor progression. Recruitment of these cells is regulated by integrins, a family of adhesion receptors that includes integrin CD11b. Here we report that, unexpectedly, integrin CD11b does not regulate myeloid cell recruitment to tumors but instead controls myeloid cell polarization and tumor growth. CD11b activation promotes pro-inflammatory macrophage polarization by stimulating expression of microRNA Let7a. In contrast, inhibition of CD11b prevents Let7a expression and induces cMyc expression, leading to immune suppressive macrophage polarization, vascular maturation, and accelerated tumor growth. Pharmacological activation of CD11b with a small molecule agonist, Leukadherin 1 (LA1), promotes pro-inflammatory macrophage polarization and suppresses tumor growth in animal models of murine and human cancer. These studies identify CD11b as negative regulator of immune suppression and a target for cancer immune therapy.
Highlights
Myeloid cells are recruited to damaged tissues where they can resolve infections and tumor growth or stimulate wound healing and tumor progression
We previously reported that the VCAM receptor integrin α4β1 promotes myeloid cell recruitment from the bone marrow to the tumor microenvironment, thereby stimulating immune suppression, angiogenesis and tumor progression[2,13,14,15]
In contrast to its role in regulating recruitment of myeloid cells to tissues during acute inflammation[16,17,18], we found that CD11b, a myeloid cell integrin receptor for ICAM-1 and fibrinogen, does not affect myeloid cell recruitment to tumors, as global deletion of CD11b in Itgam−/− mice has no effect on the number of myeloid cells in circulation or in the number of cell recruited to tumors (Supplementary Figure 1; Supplementary Figure 2a-d)
Summary
Myeloid cells are recruited to damaged tissues where they can resolve infections and tumor growth or stimulate wound healing and tumor progression Recruitment of these cells is regulated by integrins, a family of adhesion receptors that includes integrin CD11b. Pharmacological activation of CD11b with a small molecule agonist, Leukadherin 1 (LA1), promotes pro-inflammatory macrophage polarization and suppresses tumor growth in animal models of murine and human cancer. These studies identify CD11b as negative regulator of immune suppression and a target for cancer immune therapy. We show that a small molecule CD11b agonist, Leukadherin 1, inhibits anti-inflammatory macrophage polarization to suppress tumor growth and enhance survival in animal models of murine and human cancer
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