CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation – A target for novel cancer therapy

doi:10.1016/j.ctrv.2017.11.007

Cancer Treatment Reviews

Volume 63, February 2018, Pages 40-47

https://doi.org/10.1016/j.ctrv.2017.11.007 Get rights and content

Highlights

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Chemokines induce chemotaxis, promote differentiation of immune cells, and cause tissue extravasation.
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The CXCL9, -10, -11/CXCR3 axis regulates immune cell migration, differentiation, and activation through paracrine axis.
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The axis induces tumor growth and metastasis through autocrine axis.
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Preclinical researches are defining the axis as a promising target for cancer treatment.
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Other immune consistent pathways strongly crosslink with this axis.

Abstract

Chemokines are proteins which induce chemotaxis, promote differentiation of immune cells, and cause tissue extravasation. Given these properties, their role in anti-tumor immune response in the cancer environment is of great interest. Although immunotherapy has shown clinical benefit for some cancer patients, other patients do not respond. One of the mechanisms of resistance to checkpoint inhibitors may be chemokine signaling. The CXCL9, -10, -11/CXCR3 axis regulates immune cell migration, differentiation, and activation, leading to tumor suppression (paracrine axis). However, there are some reports that show involvements of this axis in tumor growth and metastasis (autocrine axis). Thus, a better understanding of CXCL9, -10, -11/CXCR3 axis is necessary to develop effective cancer control. In this article, we summarize recent evidence regarding CXCL9, CXCL10, CXCL11/CXCR3 axis in the immune system and discuss their potential role in cancer treatment.

Introduction

Chemokines are small proteins (8–15 kD) which interact with a subset of G protein-coupled receptors. They play key roles to induce chemotaxis, promote differentiation and multiplication of leukocytes, and cause tissue extravasation [1]. In 1987, Yoshimura et al. first reported about CXCL8 (IL-8), which regulates neutrophil trafficking [2]. Since then, much attention has been devoted to understanding the functions and role of chemokines in immune response. The CXCL9, -10, -11/CXCR3 axis has been a major focus of research, since it regulates differentiation of naive T cells to T helper 1 (Th1) cells and leads migration of immune cells to their focal sites [3]. Due to this pivotal role, this axis is essential for immune system on command. Recent data has suggested its clinical significance, but little is known about clinical outcomes in patients with cancer.

The CXCL9, -10, -11/CXCR3 axis mainly regulates immune cell migration, differentiation, and activation. Immune reactivity occurs through this axis by recruitment of immune cells, such as cytotoxic lymphocytes (CTLs), natural killer (NK) cells, NKT cells, and macrophages. Furthermore, Th1 polarization by this axis also activates the immune cells in response to IFN-γ [4]. Tumor-infiltrating lymphocytes are a key for good clinical outcomes and prediction of the response to existing checkpoint inhibitors [5], [6]. However, in vivo studies suggest the axis plays a tumorigenic role as well by increasing tumor proliferation and metastasis [7], [8]. Thus, a better understanding of this axis in the tumor environment is necessary to discover its role as a potential target for immunotherapy or as a predictive indicator for existing cancer treatments.

In this review, we discuss the current evidence about the role of the CXCL9, -10, -11/CXCR3 axis in tumor environment (TME) and immune response, and discuss the opportunities for novel therapies.

Section snippets

The expression and implication of CXCL9, CXCL10, CXCL11 and CXCR3

Immune cells are regulated by many different cytokines (including chemokines) not only for differentiation, but also for promptly infiltrating focal tissues through chemotactic gradients. The selection of immune cells that respond to chemotaxes is based on their surface receptors. Therefore, discrimination of the chemotactic gradients must be affected by the complicated interactions between cytokines and their receptors. CXCL9, -10, -11 are selective ligands for CXCR3. The ligands are usually

CXCL9, CXCL10, CXCL11/ CXCR3 axis for immune response

This axis works primarily for immune cell migration, differentiation, and activation. Immune reactivity for each disorder is dependent on the types of leukocytes infiltrating the focal sites. Therefore, it is critical to understand which immune cells are involved in migration, differentiation, and activation through this axis. The axis also acts directly on cancer cells and promotes cancer cell proliferation and metastasis (Fig. 1).

For immune cell migration, each of the CXCR3 ligands are

CXCL9, CXCL10, CXCL11/ CXCR3 axis, a target for cancer treatment

The CXCL9, -10, -11/ CXCR3 axis is a promising target for drug development by activating the paracrine axis, and inhibiting the autocrine axis. Agents that augment paracrine CXCL9, -10, -11 expression, and deactivate CXCR3 expression on cancer cells have shown anti-tumor activity in several tumor models (Table 1).

The use of ligands that attract Th1 cells, CTLs, NK cells, NKT cells, and M1 macrophages into tumor sites can serve as an effective anti-tumor strategy. Zhang et al. reported that the

CXCL9, CXCL10, CXCL11/ CXCR3 axis, an enhancer for other immune pathways

Although the clinical relevance of the IFN-γ/CXCL9, -10, -11/CXCR3 axis is getting established, it is critical to understand how this pathway crosslinks with other immune consistent pathways (Table 2).

The relationship between CXCL9, -10, -11/CXCR3 axis and the PDL-1/PD-1 axis is an important area of research. Programmed cell death-1 (PD-1) is heavily expressed on T cells at the tumor site than on T cells present in the peripheral blood [77], and anti-PD-1 therapy can inhibit “immune escape” and

Concluding remarks

The current review paid attention to exploring the role of CXCL9, -10, -11/ CXCR3 axis in TME and immune response. This axis plays a critical role in immune activation through paracrine signaling, impacting efficacy of cancer treatments. Based on pre-clinical data, the combination of pharmacological ligands and inhibition of CXCR3A may lead to new opportunities for more efficient immune therapies, and enhance the effectiveness of existing chemotherapies. Further understanding of the regulation

Conflict of interest

H.-J. Lenz is a consultant/advisory board member for Bayer, Boehringer Ingelheim, Celgene, Merck Serono, and Roche. No potential conflicts of interest were disclosed by the other authors.

Presentation

We have not presented this review anywhere.

Funding

R Tokunaga was supported by the Uehara Memorial Foundation. Martin D. Berger received a grant from the Swiss Cancer League (BIL KLS-333402 2014) and the Werner and Hedy Berger-Janser Foundation for cancer research. H.-J. Lenz was supported by the NIH (P30CA014089-27S1), the Gloria Borges Wunderglo Project, the Dhont Family Foundation, and the Daniel Butler Research Fund.

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Anti-Tumour TreatmentCXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation – A target for novel cancer therapy

Highlights

Abstract

Introduction

Section snippets

The expression and implication of CXCL9, CXCL10, CXCL11 and CXCR3

CXCL9, CXCL10, CXCL11/ CXCR3 axis for immune response

CXCL9, CXCL10, CXCL11/ CXCR3 axis, a target for cancer treatment

CXCL9, CXCL10, CXCL11/ CXCR3 axis, an enhancer for other immune pathways

Concluding remarks

Conflict of interest

Presentation

Funding

Adv Immunol

J Biol Chem

Blood

J Biol Chem

Blood

Cytokine

J Biol Chem

J Biol Chem

J Biol Chem

J Immunol Methods

Blood

Biomed Pharmacother

Mod Pathol

Biochem Biophys Res Commun

Role of chemokines and chemokine receptors in shaping the effector phase of the antitumor immune response

Cancer Res

Purification of a human monocyte-derived neutrophil chemotactic factor that has peptide sequence similarity to other host defense cytokines

PNAS

The CXC chemokines IP-10 and Mig are necessary for IL-12-mediated regression of the mouse RENCA tumor

J Immunol

PD-1 blockade induces responses by inhibiting adaptive immune resistance

Nature

Expansion of tumor-infiltrating CD8+ T cells Expressing PD-1 improves the efficacy of adoptive T-cell therapy

Cancer Res

Organ-specific inhibition of metastatic colon carcinoma by CXCR3 antagonism

Br J Cancer

CXCR3 as a molecular target in breast cancer metastasis: inhibition of tumor cell migration and promotion of host anti-tumor immunity

Oncotarget

Tumor necrosis factor-alpha induces cell type and tissue-specific expression of chemoattractant cytokines in vivo

Am J Pathol

The CXCL10/CXCR3 axis mediates human lung mast cell migration to asthmatic airway smooth muscle

Am J Respir Crit Care Med

Mig and IP-10: CXC chemokines that target lymphocytes

J Leukoc Biol

CXC chemokine ligand 9/monokine induced by IFN-gamma production by tumor cells is critical for T cell-mediated suppression of cutaneous tumors

J Immunol

CXCL9, but not CXCL10, promotes CXCR3-dependent immune-mediated kidney disease

J Am Soc Nephrol

Modular activation of nuclear factor-kappaB transcriptional programs in human diabetic nephropathy

Diabetes

Role of double-stranded RNA pattern recognition receptors in rhinovirus-induced airway epithelial cell responses

J Immunol

Definitive chemoradiation alters the immunologic landscape and immune checkpoints in head and neck cancer

Br J Cancer

Both CXCR3 and CXCL10/IFN-inducible protein 10 are required for resistance to primary infection by dengue virus

J Immunol

Interferon-inducible T cell alpha chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3

J Exp Med

A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development

J Exp Med

Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes

J Exp Med

Induction of the chemokine receptor CXCR3 on TCR-stimulated T cells: dependence on the release from persistent TCR-triggering and requirement for IFN-gamma stimulation

Eur J Immunol

Rules of chemokine receptor association with T cell polarization in vivo

J Clin Invest

Structure and function of the murine chemokine receptor CXCR3

Eur J Immunol

An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4

J Exp Med

Identification and partial characterization of a variant of human CXCR3 generated by posttranscriptional exon skipping

J Immunol

Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming

Nat Immunol

Expression and agonist responsiveness of CXCR3 variants in human T lymphocytes

Immunology

Chemoattractant receptors BLT1 and CXCR3 regulate antitumor immunity by facilitating CD8+ T cell migration into tumors

Anti-Tumour Treatment
CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation – A target for novel cancer therapy