Hypoxia: A Key Feature of the Tumor Microenvironment Triggers Several Mechanisms of Evasion from Natural Killer and Cytotoxic T Lymphocytes Surveillance

Review Article

J Immun Res. 2014;1(2): 7.

Hypoxia: A Key Feature of the Tumor Microenvironment Triggers Several Mechanisms of Evasion from Natural Killer and Cytotoxic T Lymphocytes Surveillance

Mgrditchian T1, Arakelian T1, Paggetti J1, Viry E1, Al-Absi A2, Medves S1, Moussay E1, Berchem G1,3, Thomas C2 and Janji B1*

11Laboratory of Experimental Hemato-Oncology, Department of Oncology, Public Research Center for Health

2Laboratory of Cellular and Molecular-Oncology, Department of Oncology, Public Research Center for Health, Luxembourg

3Centre Hospitalier de Luxembourg, Department of Hemato-Oncology, Luxembourg

*Corresponding author: Bassam Janji, Laboratory of Experimental Hemato-Oncology, Department of Oncology, Public Research Center for Health, Luxembourg

Received: November 04, 2014; Accepted: November 18, 2014; Published: November 20, 2014

Abstract

Since many years, the tumor microenvironment is recognized as an important promoter of cancer initiation and progression. Although tumors primarily consist in cancer cells, various components/factors of the microenvironment and more specifically the immune landscape, dramatically impact cancer progression. Comprehensive analyses conducted on diverse tumors have identified and characterized the most relevant components/ factors of the tumor microenvironment that support the malignant behaviorof a growing primary tumor. Tumor hypoxia is a common characteristic of the tumor microenvironment that is associated with tumor progression, metastasis, treatment failure and escape from immune surveillance. Although immune cells are usually efficiently recruited into the tumor bed, hypoxic microenvironment was reported to compromise immune cell functions and, in some cases, switch immune cell activity towards a pro-tumorigenic profile. Mechanistic studies have highlighted that hypoxia acts as double-edged sword: it simultaneously impairs the function of immune cells in the tumor microenvironment and activates intrinsic cell resistance mechanisms in tumor cells. The present article aims at reviewing some recent findings on how hypoxia impairs the anti-tumor immune response by focusing on emerging mechanisms by which hypoxia damps the function of immune effectors cells and activates intrinsic immune resistance mechanisms in tumor cells including autophagy and actin cytoskeleton remodeling.

Keywords: Cancer; Hypoxia; Immune response; Tumor microenvironment; Autophagy; Actin cytoskeleton

Abbreviations

AFs: Actin Filaments; APCs: Antigen Presenting Cells; ARP: Actin-Related Protein; ATG: Autophagy-Related Genes; Bcl-2: B Cell Lymphoma 2; CAFs: Cancer-Associated Fibroblasts; Cdc42: Cell Division Cycle 42; CTL: Cytotoxic T Lymphocyte; ECM: Extracellular Matrix; EMT: Epithelial-to-Mesenchymal Transition; FAK: Focal Adhesion Kinase; HIF: Hypoxia-Inducible Factors; HOXA1: Homeobox A1; HRE: Hypoxia-Response Element; IS, Immunological Synapse; LFA: Lymphocyte Function-Associated Antigen; MAPK: Mitogen-Activated Protein Kinases; MHC: Major Histocompatibility Complex; MICA: MHC Class I Polypeptide-Related Sequence A; miR: micro RNA; NK: Natural Killer; NKG2D: Natural Killer Group 2 Member D; PHD2: Prolyl Hydroxylase Domain Protein 2; PTPN1: Protein Tyrosine Phosphatase Non-Receptor Type 1; Rac1: Ras-Related C3 Botulinum Toxin Substrate 1; Rho: Ras Homolog; ROCK1: Rho-Associated Protein Kinase 1; STAT3: Signal Transducer and Activator of Transcription 3; TCR: T Cell Receptor; TNF: Tumor Necrosis Factor; TP53I11: Tumor Protein p53-inducible Protein 11; VEGF: Vascular Endothelial Growth Factor; VHL: Von Hippel– Lindau; WAS: Wiskott-Aldrich Syndrome; WASp: WAS Protein; YAP: Yes-associated Protein.

Introduction

Research in tumor immunology has validated the concept of cancer immune surveillance which predicts that the immune system can recognize precursors of cancer and, in most cases, destroy them or slow their growth before they become clinically apparent [1, 2]. Several types of immune cells are involved in tumor immune surveillance. Briefly, key cells of the adaptive immune system recognizing cancer cells are cytotoxic T lymphocytes (CTL) which are able to identify tumor antigens via the T cell receptor (TCR) [3]. Some of these antigens are expressed exclusively by tumors and thus are called tumor-specific antigens [3]. Natural killer (NK) cells of the innate immune system also play an important role in tumor immune surveillance [3] by mechanisms called “missing-self” and “induced-self” recognitions [5]. In addition to CTL and NK cells, macrophages and neutrophil granulocytes are also involved in antitumor immunity [6]. Macrophages are antigen presenting cells (APCs) that display tumor antigens and stimulate other immune cells such as CTL, NK cells and other APCs [7]. While the molecular mechanism by which CTL and NK cells recognize their target tumor cells is fundamentally different, both immune cells kill their target following the establishment of immunological synapse (IS) [8]. The formation of IS requires cell polarization and extensive remodeling of the actin cytoskeleton at various stages [9]. It is now well established that CTL and NK cells recognize and kill target cells by two major pathways: either through the release of cytotoxic granules containing perforin and granzymes to the cytosol of target cells [10], or through tumor necrosis factor (TNF) super family-dependent killing [11].

Many microenvironmental factors (e.g. hypoxia, composition/ organization of the extracellular matrix (ECM), inflammation, immune suppressive tumor-associated cells) contribute to various aspects of cancer progression, including immune evasion of tumor cells [12, 13]. Recently, it has been reported that the immune system also sculpts the immunogenic phenotype of an established tumor to favor the emergence of resistant tumor cell variants [14]. Accumulating experimental and clinical evidence indicates that multiple mechanisms suppressing the anti-tumor immune functions are directly evolved in the tumor microenvironment [15]. Recently, attention has been focused on the mechanisms by which hypoxic stress within the tumor microenvironment alters tumor transcriptional profiles to modulate glycolysis, proliferation, survival and invasion [16].

In this review, we focus on recent progresses in understanding the influence of hypoxic stress on the tumor survival mechanisms and tumor escape from immune surveillance. We discuss how hypoxia impairs tumor cell killing mediated by both innate and adaptive immune cells. We also review how hypoxia confers resistance to immune attack by activating intrinsic resistance mechanisms in tumor cells. Particular attention is given to hypoxia-induced immune escape mechanisms that rely on actin cytoskeleton remodeling in tumor or immune cells. Finally, we briefly address how hypoxia-targeted strategies may have potential clinical application for restoring an efficient anti-tumor immune response.

Hypoxia and Hypoxia-inducible Factors (HIF) Regulation

Hypoxic stress plays a major role in the acquisition of tumor resistance to immune cell-mediated apoptosis and in the impairment of immune cell activity. Tumor cells adapt to hypoxic microenvironment by inducing transcription factors of the hypoxia inducible factor (HIF) family [17]. The HIF family comprises three members, HIF-1,-2 and-3. HIF-1 is a hetero dimeric protein composed of a constitutively expressed HIF-1β subunit and an oxygen-regulated HIF-1α subunit. In the presence of oxygen, HIF-1α is hydroxylated on proline residue 402 and/or 564 by prolyl hydroxylase domain protein 2 (PHD2). Hydroxylated HIF-1α interacts with the Von Hippel–Lindau (VHL) tumor suppressor protein [18] and recruits an E3 ubiquitin-protein ligase to catalyze the polyubiquitination of HIF-1α and its subsequent targeting to the ubiquitin proteasome system for degradation [19] (Figure 1). Under hypoxic condition, the hydroxylation of HIF-1α is inhibited leading to HIF-1α accumulation. Subsequently, HIF-1α translocates to the nucleus, dimerizes with HIF-1β subunit, binds to the hypoxia-response elements (HRE) present in the promoter of target genes, and recruits co-activators to activate gene transcription (Figure 1). Similar to HIF-1α, HIF-2α is regulated by oxygen-dependent hydroxylation [20]. Although they share structurally similar DNA-binding and dimerization domains,HIF-1α and -2α differ in their transactivation domains. Accordingly, HIF-1α and -2α share overlapping target genes, and each also regulates a set of specific targets [21]. HIF-3α lacks the transactivation domain and was proposed to function as an inhibitor of HIF-1α and HIF-2α. Interestingly, its expression is transcriptionally regulated by HIF-1[22].

Citation: Mgrditchian T, Arakelian T, Paggetti J, Viry E, Al-Absi A, Medves S, et al. Hypoxia: A Key Feature of the Tumor Microenvironment Triggers Several Mechanisms of Evasion from Natural Killer and Cytotoxic T Lymphocytes Surveillance. J Immun Res. 2014;1(2): 7. ISSN:2471-0261