Fine-tuning Tumor Immunity with Integrin Trans-regulation

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...

Full description

Saved in:
Bibliographic Details
Published in:Cancer immunology research 2015-06, Vol.3 (6), p.661-667
Main Authors: Cantor, Joseph M, Rose, David M, Slepak, Marina, Ginsberg, Mark H
Format: Article
Language:English
Subjects:
Animals
Chemotaxis, Leukocyte - immunology
Disease Models, Animal
Humans
Integrin alpha4 - genetics
Integrin alpha4 - metabolism
Integrins - genetics
Integrins - metabolism
Lymphocyte Function-Associated Antigen-1 - genetics
Lymphocyte Function-Associated Antigen-1 - metabolism
Mice
Mice, Transgenic
Mutation
Neoplasms - genetics
Neoplasms - immunology
Neoplasms - metabolism
Neoplasms - pathology
Protein Binding
T-Lymphocyte Subsets - immunology
T-Lymphocyte Subsets - metabolism
Tumor Burden
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2326-6066
2326-6074
DOI:10.1158/2326-6066.CIR-13-0226