IL-7 promotes CXCR3 ligand-dependent T cell antitumor reactivity in lung cancer.
We are evaluating the immune enhancing activities of cytokines for their optimum utility in augmenting cellular immune responses against lung cancer. In this study, we evaluated the mechanism of antitumor responses following IL-7 administration to mice bearing established Lewis lung cancer. IL-7 decreased tumor burden with concomitant increases in the frequency of CD4 and CD8 T lymphocyte subsets, T cell activation markers CXCR3, CD69, and CD127(low), effector memory T cells, and T cell cytolytic activity against parental tumor cells. Accompanying the antitumor responses were increases in IFN-gamma, CXCL9, CXCL10, and IL-12. Individual neutralization of CD4, CD8 T lymphocytes, or the CXCR3 ligands CXCL9 and CXCL10 reversed the antitumor benefit of IL-7, indicating their importance for optimal responses in vivo. Furthermore, IL-7 decreased the tumor-induced apoptosis of T cells with subsequent decrease of the proapoptotic marker Bim. We assessed the impact of IL-7 treatment on regulatory T cells that negatively impact antitumor immune responses. IL-7 decreased regulatory T Foxp3 as well as cell suppressive activity with a reciprocal increase in SMAD7. These results indicate that IL-7 induces CXCR3 ligand-dependent T cell antitumor reactivity in lung cancer.
Andersson
Asa
A
Department of Medicine, University of California Los Angeles Lung Cancer Research Program, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Yang
Seok-Chul
SC
Huang
Min
M
Zhu
Li
L
Kar
Upendra K
UK
Batra
Raj K
RK
Elashoff
David
D
Strieter
Robert M
RM
Dubinett
Steven M
SM
Sharma
Sherven
S
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000276:immunology; D054357:Chemokine CXCL10 / Q000276:immunology*; D054370:Chemokine CXCL9 / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D007111:Immunity, Cellular; D015851:Interleukin-7 / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D054367:Receptors, CXCR3 / Q000276:immunology*; D016176:T-Lymphocyte Subsets; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory; D047368:Tumor Burden / Q000187:drug effects
C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D015851:Interleukin-7; D054367:Receptors, CXCR3