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Role of CXCR3 Ligands in IL-7/IL-7Ra-Fc–Mediated Antitumor Activity in Lung Cancer

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Role of CXCR3 Ligands in IL-7/IL-7Ra-Fc–Mediated Antitumor Activity in Lung Cancer Clinical Cancer Cancer Therapy: Preclinical Research Role of CXCR3 Ligands in IL-7/IL-7Ra-Fc–Mediated Antitumor Activity in Lung Cancer Asa Andersson1, Minu K. Srivastava1, Marni Harris-White3,4, Min Huang1,2,4, Li Zhu1,2,4, David Elashoff1, Robert M. Strieter5, Steven M. Dubinett1,2,4, and Sherven Sharma1,2,4 Abstract Purpose: We evaluated the utility of chimeric gc homeostatic cytokine, IL-7/IL-7Ra-Fc, to restore host APC (antigen presenting cell) and T cell activities in lung cancer. Experimental Design: Utilizing murine lung cancer models we determined the antitumor efficacy of IL- 7/IL-7Ra-Fc. APC, T cell, cytokine analyses, neutralization of CXCL9, CXCL10, and IFNg were carried out to evaluate the mechanistic differences in the antitumor activity of IL-7/IL-7Ra-Fc in comparison to controls. Results: IL-7/IL-7Ra-Fc administration inhibited tumor growth and increased survival in lung cancer. Accompanying the tumor growth inhibition were increases in APC and T cell activities. In comparison to controls, IL-7/IL-7Ra-Fc treatment of tumor bearing mice led to increased: (i) levels of CXCL9, CXCL10, IFNg, IL-12 but reduced IL-10 and TGFb, (ii) tumor macrophage infiltrates characteristic of M1 phenotype with increased IL-12, iNOS but reduced IL-10 and arginase, (iii) frequencies of T and NK cells, (iv) T cell activation markers CXCR3, CD69 and CD127low, (v) effector memory T cells, and (vi) T cell cytolytic activity against parental tumor cells. IL-7/IL-7Ra-Fc treatment abrogated the tumor induced reduction in splenic functional APC activity to T responder cells. The CXCR3 ligands played an important role in IL-7/IL- 7Ra-Fc–mediated antitumor activity. Neutralization of CXCL9, CXCL10, or IFNg reduced CXCR3 expres- sing activated T cells infiltrating the tumor and abrogated IL-7/IL-7Ra-Fc–mediated tumor growth inhibition. Conclusions: Our findings show that IL-7/IL-7Ra-Fc promotes afferent and efferent antitumor responses in lung cancer. Clin Cancer Res; 17(11); 3660–72. Ó2011 AACR. Introduction T lymphocytes (3, 4) and APC (5) leads to better prognosis in lung cancer patients. Although tumor growth and invasion leads to inflam- Interleukin IL-7 is a 17.5 kDa cytokine produced by a matory responses, the immune system generally develops variety of stromal cells, keratinocytes, dendritic cells, neu- tolerance to cancer. One way to induce potent immune rons, and endothelial cells and is essential for lymphopoi- responses against tumors is to activate key innate and esis (6), T cell homeostasis (7–9), and maintenance (10, immune effector mechanisms. Toward this end, we are 11). IL-7 also promotes T cell cytolytic and innate responses evaluating the utility of chimeric gc homeostatic cytokine, (12, 13). The biological effects of IL-7 on target cells are IL-7/IL-7Ra-Fc, to restore host APC (antigen presenting mediated by binding to the high affinity IL-7 receptor cell) and T cell activities dysregulated in cancer patients complex that is composed of the ligand binding IL-7 (1, 2). It is evident from previous studies that intra- receptor a chain and the common shared g chain (14). tumoral infiltration by relatively high numbers of activated Na€ve T cells express high levels of the IL-7 receptor CD127 and respond rapidly to IL-7 stimulation (15) making this molecule an attractive agent for restoration of T cell activ- ities in tumor bearing hosts. Our rationale for using the IL- Authors' Affiliations: 1Department of Medicine, UCLA Lung Cancer Research Program, 2Jonsson Comprehensive Cancer Center, 3David 7/IL-7Ra-Fc chimera molecule is that it combines the T Geffen School of Medicine at UCLA; 4Molecular Gene Medicine Labora- lymphocyte activation property of IL-7 with IgG Fc to tory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California; and 5Department of Medicine, University of Virginia, augment innate effectors through enhanced APC activity. Charlottesville, Virginia We anticipate that agents that activate both the innate and Corresponding Author: Sherven Sharma, Molecular Gene Medicine immune effector mechanisms will be more effective in Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, controlling tumor growth. Los Angeles, CA 90073 or Division of Pulmonary and Critical Care Medicine, University of California Los Angeles Lung Cancer Program, Despite the expression of tumor antigens by lung cancer 10833 Le Conte Ave., Los Angeles, CA 90095. Phone: 310-478-3711, cells, the limited expression of MHC antigens, defective ext 41863; Fax: 310-268-4807; E-mail: [email protected] transporter associated with antigen processing (TAP), and doi: 10.1158/1078-0432.CCR-10-3346 lack of costimulatory molecules make them ineffective APC Ó2011 American Association for Cancer Research. (16). The central importance of functional APC in the 3660 Clin Cancer Res; 17(11) June 1, 2011 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2011 American Association for Cancer Research. IL-7/IL-7Ra-Fc Inhibits Lung Cancer Growth Translational Relevance deling via inhibition of Type1 immune responses by IL-10 and TGFb secretion. The M2 macrophages express high We evaluated IL-7/IL-7Ra-Fc to restore host APC levels of IL-10 and arginase that suppress antitumor (antigen presenting cell) and T cell activities dysregu- immune responses (31–34). lated in lung cancer. Intratumoral infiltration by rela- The numbers and types of leukocytes in the tumor tively high numbers of activated T lymphocytes and infiltrate are related to the chemokines produced in the APC leads to better prognosis in lung cancer patients. tumor microenvironment. Antitumor reactivity is due to Our rationale for using the IL-7/IL-7Ra-Fc chimera the types of leukocytes infiltrating the tumors. The IFNg molecule is that it combines the T lymphocyte activa- inducible chemokines, CXCL9, and CXCL10 exert their tion property of IL-7 with IgG Fc to augment innate biological effects by binding to the 7 transmembrane effectors by enhancing APC activity. Our data show that domain G-protein coupled CXCR3 receptor (35). CXCL9 IL-7/IL-7Ra-Fc effectively promotes the afferent and and CXCL10 expression in the tumor microenvironment efferent arms of the immune response for enhanced recruit activated CXCR3 expressing effector T lymphocytes antitumor activity in lung cancer. We anticipate that with antitumor reactivity. Thus mechanisms that increase IL-7/IL-7Ra-Fc would be most beneficial to patients the levels of CXCL9 and CXCL10 in the tumor microenvir- who have their lung cancer detected early when the onment promote effective cell mediated antitumor activity tumor burden is low and innate and immune effectors through the CXCR3 expressing effector T lymphocytes. are more susceptible to modulation. We believe that Here we found that IL-7/IL-7Ra-Fc treatment induced biological agents that promote APC and T cell respon- macrophages with M1 phenotype, inhibited tumor burden siveness will be useful in addition with other and extended survival in mice bearing lung cancer. Our approaches for therapeutic intervention in lung cancer. findings show that IL-7/IL-7Ra-Fc promotes the afferent M1 macrophage phenotype and the efferent (CXCR3/ CXCR3 ligand biological axis) limbs of the immune immune response against cancer was well defined by Huang response for sustained antitumor activity in lung cancer. and colleagues (17). The study revealed that even highly immunogenic tumors require host APC for antigen presen- Materials and Methods tation. Thus host APC, rather than tumor cells, present þ þ tumor antigen to CD8 T cells. CD8 T cell responses Reagents can be induced in vivo by professional APC that present The murine Lewis lung carcinoma (3LL, H-2b, also exogenous antigens in a MHC I restricted manner (18) that known as LLC, ATCC CRL-1642) obtained from American is critical for effective antitumor responses (19). However, Type Culture Collection (ATCC) was used in these studies. in tumor bearing hosts, there is a state of T cell unrespon- The culture medium contained RPMI 1640 (Irvine Scien- siveness (20–22) through dysregulated APC activity (23). tific supplemented with 10% FBS (Gemini Bioproducts), In additional, tumor cells produce immune inhibitory penicillin (100 units/mL), streptomycin (0.1 mg/mL), and factors that promote escape from immune surveillance (24). 2 mmol/L glutamine (JRH Biosciences). Fluorescein iso- The tumor microenvironment not only fails to provide the thiocyanate-, phycoerythrin-, allophycocyanin-, PerCP- or inflammatory signals needed for efficient APC activation PerCP-Cy7-conjugated anti-mouse mAbs to CD3 (145- but also inhibits APC differentiation and maturation 2C11), CD4 (RM4-5), CD8a (53-6.7), CD69 (H1.2F3), through IL-10 (25). Immature APC produce little or no CD127 (A7R34), subclass control antibody, unconjugated IL-12 which is required to support T cell proliferation. If iNOS (6/iNOS/NOS Type II), and Arginase (19/Arginase I) APC fail to provide an appropriate costimulatory signal for were purchased from BD Biosciences. Anti-mouse mAbs to T cells, tolerance or anergy can develop (25, 26). CD44 (IM7), CD49b (DX5), IL-10 (JES5–16E3), IFNg Macrophages in the tumor microenvironment play an (XMG1.2), CCR7 (4B12), and recombinant murine IL-7 important modulatory role in the generation of antitumor (endotoxin level: less than 0.01 ng/mg cytokine as deter- responses. The production of chemotactic factors such as mined by the LAL assay) were purchased from eBioScience. CCL2, VEGF, and macrophage colony stimulating factor Antibody to mouse F4/80 (BM8) was purchased from (M-CSF; refs. 27, 28) in the tumor microenvironment BioLegend. Anti-mouse mAbs to CXCR3 (220803), recruits macrophages. The type of macrophages infiltrating IL-7Ra-Fc chimeric molecule (747-MR; endotoxin level: the tumor correlates with favorable or unfavorable prog- less than 1.0 EU/mg of protein by LAL method), ELISA noses (29).
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