HIF-2α/ITPR1 axis: A new saboteur of NK-mediated lysis

-The tumor microenvironment is a complex system, playing an important role in tumor development and progression. Besides cellular stromal components, extracellular matrix fibers, cytokines, and other metabolic mediators are also involved. In this review we outline the potential role of hypoxia, a major feature of most solid tumors, within the tumor microenvironment and how it contributes to immune resistance and immune suppression/tolerance and can be detrimental to antitumor effector cell functions. We also outline how hypoxic stress influences immunosuppressive pathways involving macrophages, myeloid-derived suppressor cells, T regulatory cells, and immune checkpoints and how it may confer tumor resistance. Finally, we discuss how microenvironmental hypoxia poses both obstacles and opportunities for new therapeutic immune interventions.hypoxia; hypoxia-inducible factor; tumor microenvironment; myeloid cells; lymphoid cells; immune suppression; cancer stem cells; programmed death-ligand 1; epithelial-mesenchymal transition; circulating tumor cells; autophagy and antitumor immune response IT HAS BECOME INCREASINGLY apparent that malignant cells exist in a complex cellular and extracellular microenvironment that plays key roles in the initiation and maintenance of the malignant phenotype. Among the microenvironmental factors that play a dominant role in neoplasia, hypoxia is believed to be one of the most relevant in the neoplastic response of tumor cells. It is widely appreciated that the majority of malignancies create a hostile hypoxic microenvironment that can hamper cellmediated immunity and dampen the efficacy of the immune response. Poorly vascularized and hypoxic zones inside solid tumors contribute to immune tolerance of tumor cells by impeding the homing of immunocompetent cells into tumors and inhibiting their antitumor efficacy. Several regulatory mechanisms can occur concurrently within the hypoxic tumor microenvironment, resulting in multiple redundant levels of immune cell plasticity and suppression, tumor plasticity, and functional heterogeneity. Hypoxic stress clearly plays a crucial role in tumor promotion and immune escape by controlling angiogenesis and favoring immune suppression and tumor resistance. Like other therapeutic attempts, immunotherapy is heavily hampered by the morphologically aberrant tumor microvasculature, preventing migration of immune effector cells into established tumors. Many strategies are emerging for changing the immunosuppressive nature of the tumor to a microenvironment able to support antitumor immunity. The identification of ways to induce a permissive and less hostile tumor microenvironment to avoid tumor resistance and immune suppression is of major interest and pertinence. Hypoxia as an Integral Component of the Tumor MicroenvironmentAll life on Earth depends on O 2 , and all physiological and pathological processes of a living cell rely principally on O 2 (103). Hypoxia is characterized by lack of O 2 , and hypoxic tissues are inadequately oxygenated (107). A p...

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“…(72). Taken together, these results suggest that inhibition of ITPR1/ autophagy in tumors improves their elimination by NK cells in vivo (71,73).…”

Section: Hypoxic Stress Impairs Tumor Target Susceptibility To Effectsupporting

confidence: 48%

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

Noman

Hasmim

Messai

et al. 2015

American Journal of Physiology-Cell Physiology

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“…This resistance required the stabilization of HIF-2α and the subsequent overexpression of the autophagy sensor inositol 1, 4, 5-trisphosphate receptor, type 1 (ITPR1). Both inhibition of BECN1 or ITPR1 in VHL-mutated ccRCC cells restored NK-mediated killing (Figure 3) (61, 62). …”

Section: Effect Of Autophagy On Antitumor Immune Responsesmentioning

confidence: 96%

Hijacker of the Antitumor Immune Response: Autophagy Is Showing Its Worst Facet

et al. 2016

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Macroautophagy (hereafter referred to as autophagy) is a housekeeping process constitutively executed at basal level in all cells to promote cellular homeostasis by regulating organelle and protein turnover. However, autophagy deregulation caused by several stress factors, such as hypoxia, is prevalent in many cancers. It is now well established that autophagy can act as tumor suppressor or tumor promoter depending on tumor type, stage, and genetic context. In developed tumors, autophagy promotes the survival of cancer cells and therefore operates as a cell resistance mechanism. Emerging evidence point to the prominent role of autophagy in disabling the antitumor immune response by multiple overlapping mechanisms leading to tumor escape from immune cell attack mediated by both natural killer cells and cytotoxic T-lymphocytes. Such a role has inspired significant interest in applying anti-autophagy therapies as an entirely new approach to overcome tumor escape from immune surveillance, which constitutes so far a major challenge in developing more effective cancer immunotherapies. In this review, we will summarize recent reports describing how tumor cells, by activating autophagy, manage to hijack the immune system. In particular, we will focus on the emerging role of hypoxia-induced autophagy in shaping the antitumor immune response and in allowing tumor cells to outmaneuver an effective immune response and escape immunosurveillance. In keeping with this, we strongly believe that autophagy represents an attractive future therapeutic target to develop innovative and effective cancer immunotherapeutic approaches.

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“…57 Taken together, these results suggest that inhibiting inositol 1,4,5-trisphosphate receptor, type 1/autophagy in tumors improves their elimination by NK cells in vivo . 11,58 …”

Section: Hypoxia Induces Resistance To Cell-mediated Cytotoxicitymentioning

confidence: 99%

“…Among these alterations, VHL mutations, which are known to be associated with 75% of renal cell carcinoma, are the most common causes of intrinsic induction of HIF-1 and HIF-2. 11 …”

Section: Introductionmentioning

confidence: 99%

Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer

et al. 2016

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Tumors use several strategies to evade the host immune response, including creation of an immune-suppressive and hostile tumor environment. Tissue hypoxia due to inadequate blood supply is reported to develop very early during tumor establishment. Hypoxic stress has a strong impact on tumor cell biology. In particular, tissue hypoxia contributes to therapeutic resistance, heterogeneity and progression. It also interferes with immune plasticity, promotes the differentiation and expansion of immune-suppressive stromal cells, and remodels the metabolic landscape to support immune privilege. Therefore, tissue hypoxia has been regarded as a central factor for tumor aggressiveness and metastasis. In this regard, manipulating host-tumor interactions in the context of the hypoxic tumor microenvironment may be important in preventing or reverting malignant conversion. We will discuss how tumor microenvironment-driven transient compositional tumor heterogeneity involves hypoxic stress. Tumor hypoxia is a therapeutic concern since it can reduce the effectiveness of conventional therapies as well as cancer immunotherapy. Thus, understanding how tumor and stromal cells respond to hypoxia will allow for the design of innovative cancer therapies that can overcome these barriers. A better understanding of hypoxia-dependent mechanisms involved in the regulation of immune tolerance could lead to new strategies to enhance antitumor immunity. Therefore, discovery and validation of therapeutic targets derived from the hypoxic tumor microenvironment is of major importance. In this context, critical hypoxia-associated pathways are attractive targets for immunotherapy of cancer. In this review, we summarize current knowledge regarding the molecular mechanisms induced by tumor cell hypoxia with a special emphasis on therapeutic resistance and immune suppression. We emphasize mechanisms of manipulating hypoxic stress and its associated pathways, which may support the development of more durable and successful cancer immunotherapy approaches in the future.

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HIF-2α/ITPR1 axis: A new saboteur of NK-mediated lysis

Cited by 12 publications

References 10 publications

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

Hijacker of the Antitumor Immune Response: Autophagy Is Showing Its Worst Facet

Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer

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