title: Fine-tuning Tumor Immunity with Integrin Trans-regulation.
abstract: Inefficient T-cell homing to tissues limits adoptive T-cell immunotherapy of solid tumors. αLβ2 and α4β1 integrins mediate trafficking of T cells into tissues via engagement of ICAM-1 and VCAM-1, respectively. Inhibiting protein kinase A (PKA)-mediated phosphorylation of α4 integrin in cells results in an increase in αLβ2-mediated migration on mixed ICAM-1-VCAM-1 substrates in vitro, a phenomenon termed "integrin trans-regulation." Here, we created an α4(S988A)-bearing mouse, which precludes PKA-mediated α4 phosphorylation, to examine the effect of integrin trans-regulation in vivo. The α4(S988A) mouse exhibited a dramatic and selective increase in migration of lymphocytes, but not myeloid cells, to sites of inflammation. Importantly, we found that the α4(S988A) mice exhibited a marked increase in T-cell entry into and reduced growth of B16 melanomas, consistent with antitumor roles of infiltrating T cells and progrowth functions of tumor-associated macrophages. Thus, increased α4 trans-regulation of αLβ2 integrin function biases leukocyte emigration toward lymphocytes relative to myeloid cells and enhances tumor immunity.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California. jmcantor@ucsd.edu mhginsberg@ucsd.edu.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Cantor
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California.
authors.forename: David M
authors.initials: DM
authors.lastname: Rose
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California.
authors.forename: Marina
authors.initials: M
authors.lastname: Slepak
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California. jmcantor@ucsd.edu mhginsberg@ucsd.edu.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
mesh_terms: D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D039441:Integrin alpha4 / Q000235:genetics / Q000378:metabolism; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D039441:Integrin alpha4