Improving Cancer Immunotherapy by Targeting the Hypoxic Tumor Microenvironment: New Opportunities and Challenges

Noman, Muhammad Zaeem; Hasmim, Meriem; Lequeux, Audrey; Xiao, Malina; Duhem, Caroline; Chouaı̈b, Salem; Berchem, Guy; Janji, Bassam

doi:10.3390/cells8091083

Cited by 165 publications

(156 citation statements)

References 104 publications

(116 reference statements)

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“…Since HIF-1α is a poor prognosis indicator which also promotes other adverse treatment outcomes, such as chemo and radioresistance, targeting HIF-1α shall increase treatment efficacy and limit metastasis in cancers (144). Inhibiting HIF-1α in different cancer types have found to effectively limit metastasis in both in vitro and in vivo experiments (145). However, there is a lack of selective HIF-1 inhibitors and clinical trials in this area (145).…”

Section: Future Perspectivesmentioning

confidence: 99%

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Hypoxia-Induced Epithelial-Mesenchymal Transition in Cancers: HIF-1α and Beyond

2020

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Metastasis is the main cause of cancer-related mortality. Although the actual process of metastasis remains largely elusive, epithelial-mesenchymal transition (EMT) has been considered as a major event in metastasis. Besides, hypoxia is common in solid cancers and has been considered as an important factor for adverse treatment outcomes including metastasis. Since EMT and hypoxia potentially share several signaling pathways, many recent studies focused on investigate the issue of hypoxia-induced EMT. Among all potential mediators of hypoxia-induced EMT, hypoxia-inducible factor-1α (HIF-1α) has been studied extensively. Moreover, there are other potential mediators that may also contribute to the process. This review aims to summarize the recent reports on hypoxia-induced EMT by HIF-1α or other potential mediators and provide insights for further investigations on this issue. Ultimately, better understanding of hypoxia-induced EMT may allow us to develop anti-metastatic strategies and improve treatment outcomes.

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Section: Future Perspectivesmentioning

confidence: 99%

“…Inhibiting HIF-1α in different cancer types have found to effectively limit metastasis in both in vitro and in vivo experiments (145). However, there is a lack of selective HIF-1 inhibitors and clinical trials in this area (145). Thus, the clinical potential of this treatment strategy is yet to be revealed.…”

Section: Future Perspectivesmentioning

confidence: 99%

Hypoxia-Induced Epithelial-Mesenchymal Transition in Cancers: HIF-1α and Beyond

2020

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“…Cancer is considered to be a disease of tumor microenvironment [13]. Tumor microenvironment is a complex and dynamic cell population, which is composed of tumor epithelial cells, tumor immune cells, broblasts, immunosuppressive cells, adipocytes, endothelial cells and so on.…”

Section: Discussionmentioning

confidence: 99%

The Role of CBLL1 in the Prognosis and Immune Infiltration of Pan-Cancer

Guo

et al. 2020

Preprint

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ObjectiveThis study aims to explore the role of CBLL1 in pan-carcinoma and tumor immune infiltrates. MethodsDownload mRNA expression, mutation and clinical data in UCSC database, to analyze the relationship between CBLL1 expression and clinicopathological vlaue, and immune microenvironment in pan-cancer. CIBERSORT was used to analyze the relationship between CBLL1 expression and the infiltration of pan-carcinoma immune cells. The mRNA expression data of UCSC database were used to analyze the correlation between CBLL1 expression and pan-cancer immunomodulations, checkpoints and receptor molecules. ResultsThe levels of CBLL1 mRNA expression in pan-cancer tissues were abnormal. The level of CBLL1 is related to the age, race, clinical stage and treatment effect of patients with pan-carcinoma and associated with the prognosis of patients with KIRC, LUSC, THCA, THYM, MESO, PRAD, STAD, and UVM. Univariate COX regression analysis showed that expression of CBLL1 was a risk factor for poor prognosis in patients with KICH, KIRC, LAML, THYM, KIRC, PCPG, OV, PRAD, STAD, GBM and UVM. The expression level of CBLL1 was correlated with BLCA, BRCA, COAD, LAML, LGG, LUAD, LUSC, SARC, STAD, THCA, THYM and UVM tumor mutational burden, and with ACC, BRCA, CESC, COAD, DLBC, HNSC, PRAD, READ, SARC, STAD, TGCT, THCA and UCEC microsatellite instability. The expression level of CBLL1 was correlated with cancer stromal cells and immune cells. The expression of CBLL1 is related to pan-cancer immunomodulators, checkpoints and receptor molecules. ConclusionCBLL1 is abnormally expressed in patients with pan-carcinoma, which is expected to be a biomarker for prognosis, mutation and immune infiltration in patients with pan-carcinoma.

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“…Through HIF-1α, hypoxia results in upregulated expression of programmed death ligand 1 (PD-L1) in tumor cells as well as immune cells such as macrophages. [40,41] The binding between PD-L1/L2 and the receptor PD-1 eventually lead to T cell exhaustion and decline in cytotoxic function. [41] The abnormal vasculature arising from tumor angiogenesis has also been viewed as further preserving the hypoxic microenvironment through its limited nutrient delivery, hence sustaining hypoxia-induced signaling and consequent immunotherapy challenges.…”

Section: The Complicated Hypoxic Tumor Microenvironmentmentioning

confidence: 99%

“…[40,41] The binding between PD-L1/L2 and the receptor PD-1 eventually lead to T cell exhaustion and decline in cytotoxic function. [41] The abnormal vasculature arising from tumor angiogenesis has also been viewed as further preserving the hypoxic microenvironment through its limited nutrient delivery, hence sustaining hypoxia-induced signaling and consequent immunotherapy challenges. [42,43] In one study of cancer patients' cellular immunome, regulatory T cells made up around 50% of all CD4+ T cells in examined melanoma tumor samples, which the authors proposed as contributing to therapeutic challenges.…”

Section: The Complicated Hypoxic Tumor Microenvironmentmentioning

confidence: 99%

Retooling Cancer Nanotherapeutics’ Entry into Tumors to Alleviate Tumoral Hypoxia

Sun

et al. 2020

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The contribution of the TME in the progress of the malignant tumor is significant and now also increasingly recognized to affect the efficiencies of drug delivery and distribution within tumors. [8] Hypoxia is the phenomenon where the oxygen supplied through the usually aberrant tumor blood vessels are insufficient to consistently meet the growing tumor's metabolic needs. [9] Hypoxia occurs in tumors due to insufficient oxygen supply in relation to the tumors' metabolism and includes: a) acute hypoxia, the result of poor blood perfusion caused by abnormal, aberrant vasculature, giving rise to tortuous network organization, irregular flow pattern, [4] and b) chronic hypoxia, the cause and the result of a sparse vascular density in the tumor, giving rise to insufficient oxygen delivered to tumor cells spatially distant from blood vessels. Compensatory angiogenesis itself is also regarded as the result of mainly nutrient and oxygen deprivation as the tumor grows. [10] Hence, hypoxia is an element in the TME that is closely interconnected with pathological angiogenesis and extracellular matrix in cancer. In general, cells are sensitive to low oxygen conditions, which activate the hypoxia-inducible factor (HIF) family of transcriptional factors to allow for expression of genes that may enhance tumor survival under the hypoxic environment. One consequential outcome is the accumulation of vascular endothelial growth factor (VEGF) under transcription by HIF-1α, resulting in the induction of angiogenesis. [11] Under hypoxia, the oxygen-dependent subunit of HIF-1, HIF-1α, is successfully accumulated (otherwise degraded in normoxic conditions) to dimerize with an oxygen-independent subunit to form the HIF-1 dimer. [4] HIF-1 then upregulates dozens of genes that allows for both adaptation and long-term expansion of the tumor cells. [12] Hypoxia is a critical factor to examine, as there is increasing recognition of its role as a potential target during cancer therapy, although the dual role of HIFs in both promoting survival and apoptosis poses a challenge for certain tumor types and cases. [13] 1.2. Hypoxia Aggravates the Challenges for Cancer Therapy A major consequence of hypoxia is the occurrence of hypoxiainduced metastasis. Hypoxia and metastasis have been Anti-hypoxia cancer nanomedicine (AHCN) holds exciting potential in improving oxygen-dependent therapeutic efficiencies of malignant tumors. However, most studies regarding AHCN focus on optimizing structure and function of nanomaterials with presupposed successful entry into tumor cells. From such a traditional perspective, the main barrier that AHCN needs to overcome is mainly the tumor cell membrane. However, such an oversimplified perspective would neglect that real tumors have many biological, physiological, physical, and chemical defenses preventing the current state-of-the-art AHCNs from even reaching the targeted tumor cells. Fortunately, in recent years, some studies are beginning to intentionally focus on overcoming physiological barriers to alleviate hypoxi...

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Improving Cancer Immunotherapy by Targeting the Hypoxic Tumor Microenvironment: New Opportunities and Challenges

Cited by 165 publications

References 104 publications

Hypoxia-Induced Epithelial-Mesenchymal Transition in Cancers: HIF-1α and Beyond

Hypoxia-Induced Epithelial-Mesenchymal Transition in Cancers: HIF-1α and Beyond

The Role of CBLL1 in the Prognosis and Immune Infiltration of Pan-Cancer

Retooling Cancer Nanotherapeutics’ Entry into Tumors to Alleviate Tumoral Hypoxia

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