Integrating tumor hypoxic stress in novel and more adaptable strategies for cancer immunotherapy

Khouzam, Raefa Abou; Venkatesh, Goutham Hassan; Zaarour, Rania F.; Chamseddine, Ali N.; Francis, Amirtharaj; Buart, Stéphanie; Terry, Stéphane; Chouaı̈b, Salem

doi:10.1016/j.semcancer.2020.01.003

Cited by 66 publications

(69 citation statements)

References 206 publications

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“…In our study, hypoxia gave rise to increased drug resistance and an elevated level of genetic markers associated with stemness. Recent research supports the role of hypoxia in the stemness of cancer cells [31,32]. In particular, HIF-1α has been found to promote the stemness of cancer cells through the regulation of several pathways, including PI3K/Akt/mTOR [26], Wnt/β-catenin [33], and Notch [34] signaling.…”

Section: Discussionmentioning

confidence: 94%

Hypoxia-induced Tie1 Drives Stemness and Cisplatin Resistance in Non-small Cell Lung Carcinoma Cells

Yang

Chen

et al. 2020

Preprint

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Background: Drug resistance and metastasis involving hypoxic tumor environment and persistent stem cell populations are detrimental to the survival of patients with non-small cell lung carcinoma (NSCLC). Tie1 is upregulated in hypoxia and is believed to counteract the effectiveness of platinum agents, by promoting the stemness properties in cells. We have investigated the association of Tie1 with HIF-1α and cisplatin resistance in NSCLC cell lines. Methods: Expression of Tie1 in a pulmonary microvascular endothelial cell line (HPMEC) and in NSCLC cell lines was detected using qRT-PCR and western blot. The effect of Tie1 on cell stemness and migration was examined by sphere-forming assay and transwell assay in NSCLC cells with Tie1 silenced. The regulation of Tie1 by HIF-1α was evaluated by a dual-luciferase reporter assay and chromatinImmune precipitation (ChIP) analysis.Results: We found that hypoxia could induce stemness and cisplatin resistance in vitro. Tie1 was expressed at low levels in NSCLC cells when compared with human pulmonary microvascular endothelial cells, however, its expression was increased by hypoxia. Additionally, Tie1 knockdown could reduce the stemness properties and increase sensitivity to cisplatin in vitro and in a xenograft mouse model. The promoter of Tie1 contains two predicted hypoxia-response elements (HREs). We mutated both HRE sites and conducted chromatin immune-precipitation and promoter luciferase reporter assays and were able to conclude that the induction of Tie1 by hypoxia was HIF-1α-dependent. Conclusions: Our findings indicated that Tie1 is upregulated in a hypoxic environment by HIF-1α and contributes to tumorigenesis and cisplatin resistance through the promotion of stemness in NSCLC cells.

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Section: Discussionmentioning

confidence: 94%

Hypoxia-induced Tie1 Drives Stemness and Cisplatin Resistance in Non-small Cell Lung Carcinoma Cells

Yang

Chen

et al. 2020

Preprint

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“…This highly speculative hypothesis may be reasonable for two reasons. First, hypoxia is an inherent feature of the tumor microenvironment (TME), and a key player governing various cancer hallmarks [36,37]. Additionally, it has been well documented that over 90% of ccRCC is closely associated with VHL mutations, which results in stabilization of hypoxia inducible factors (HIF) [4,38].…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer Analysis Combining with Experiments Indicates the Sensitivity of Renal Carcinogenesis to DLGAP5 Expression

Feng

Guo

et al. 2020

Preprint

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Background: Discs large-associated protein 5 (DLGAP5), a kinetochore ﬁbers-binding protein, has been found to function as a oncoprotein in many cancers. However, its expression patterns in normal and cancer tissues across pan-cancer, as well as the cell lines, are far from clear. Methods: Data from genotype-tissue expression (GTEx) and The Cancer Genome Atlas (TCGA) was used to analyze the DLGAP5 expression in normal tissues and cancer cell lines, respectively. The analysis of DLGAP5 expression in cancer tissues and adjacent tissues was based on data from a combined TCGA and GTEx. The associations between the expression, prognosis and cancer immune infiltrates in pan-cancer were also investigated based on TCGA and Tumor Immune Estimation Resource (TIMER), respectively. Furthermore, the analysis results of ccRCC was verified using cell lines via RNAi, western blotting, and the cytological analysis.Results: The low expression levels of DLGAP5 were observed in 31 types of common human tissues, including kidney tissue. However, its expression displayed upregulation in all the 21 tested cancer cell lines, of which kidney cancer cell lines showed a minimal upregulation. As predicted, the significant overexpression of DLGAP5 occurred in at least 26 types of common cancer tissues compared with the adjacent normal tissues. Surprisingly, in three types of kidney cancer (KICH, KIRC/ccRCC, KIRP), DLGAP5 exhibited a statistically significant, but minor, overexpression among 26 types of tested cancers. Furthermore, the survival probability of some tested cancers, including kidney cancer, were significantly related to the upregulated expression of DLGAP5. In addition, among 33 types of tested cancers, KIRC/ccRCC, LGG and LIHC showed a significant positive correlation between DLGAP5 expression and immune infiltration levels. DLGAP5 expression level was also significantly positive correlated with clinical TNM stage of ccRCC patients. Regarding ccRCC tissues and the cell lines, upregulation expression of DLGAP5 was also detected. Its knockdown inhibited the cells viability and proliferation, and compromised the cells migration and invasion. Conclusions: DLGAP5 overexpression occurred in common human cancers, including the kidney cancers. Notably, ccRCC, seemed to be particularly sensitive to the expression. DLGAP5, therefore, may be as a robust independent prognostic biomarker in ccRCC diagnosis.

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“…It has been confirmed that oxygen therapy as an immunological co-adjuvant combined with other existing immunotherapies can decrease the tumor hypoxia and HIF-1α-CD39/CD73-driven extracellular adenosine accumulation. Together, this strategy functions to weaken the A2AR/A2BR-mediated pleiotropic cascade of immunosuppression in the hypoxic TME [12,104]. Hatfield reported that respiratory hyperoxia with 60% oxygen enhances intra-tumoral infiltration and decreases inhibition of CTLs, promoting pulmonary tumor extinction induced by dual inhibition of PD-1 and CTLA-4 [95].…”

Section: Supplemental Oxygenationmentioning

confidence: 99%

“…Moreover, emerging evidence has indicated that hypoxia can cause tumor resistance to immunotherapy by several mechanisms, involving both innate and adaptive immunity. Hypoxia-driven adaptive mechanisms allow tumor cells to continue to survive and even proliferate in the hypoxic TME while also creating an inhospitable environment for immune cells and damaging key regulatory pathways [12]. Hypoxia can induce immune tolerance and immune escape by interfering with tumor killing functions of effector cells and preventing their homing to the TME [13].…”

Section: Introductionmentioning

confidence: 99%

“…Hypoxia can induce immune tolerance and immune escape by interfering with tumor killing functions of effector cells and preventing their homing to the TME [13]. Hypoxia can also promote immune-suppressive stromal cell differentiation and increase immunosuppressive factors, including checkpoint molecules, as well as modify the metabolic landscape [12]. Currently available biomarkers to predict immunotherapy efficacy mainly include PD-L1, tumor mutational burden (TMB), and microsatellite instability/deficient mismatch repair (MSI/dMMR); however, the problem of "poor soil" is often ignored [14].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting hypoxia in the tumor microenvironment: a potential strategy to improve cancer immunotherapy

Wang

Zhao

Zhang

et al. 2021

J Exp Clin Cancer Res

163

137

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With the success of immune checkpoint inhibitors (ICIs), significant progress has been made in the field of cancer immunotherapy. Despite the long-lasting outcomes in responders, the majority of patients with cancer still do not benefit from this revolutionary therapy. Increasing evidence suggests that one of the major barriers limiting the efficacy of immunotherapy seems to coalesce with the hypoxic tumor microenvironment (TME), which is an intrinsic property of all solid tumors. In addition to its impact on shaping tumor invasion and metastasis, the hypoxic TME plays an essential role in inducing immune suppression and resistance though fostering diverse changes in stromal cell biology. Therefore, targeting hypoxia may provide a means to enhance the efficacy of immunotherapy. In this review, the potential impact of hypoxia within the TME, in terms of key immune cell populations, and the contribution to immune suppression are discussed. In addition, we outline how hypoxia can be manipulated to tailor the immune response and provide a promising combinational therapeutic strategy to improve immunotherapy.

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Integrating tumor hypoxic stress in novel and more adaptable strategies for cancer immunotherapy

Cited by 66 publications

References 206 publications

Hypoxia-induced Tie1 Drives Stemness and Cisplatin Resistance in Non-small Cell Lung Carcinoma Cells

Hypoxia-induced Tie1 Drives Stemness and Cisplatin Resistance in Non-small Cell Lung Carcinoma Cells

Pan-cancer Analysis Combining with Experiments Indicates the Sensitivity of Renal Carcinogenesis to DLGAP5 Expression

Targeting hypoxia in the tumor microenvironment: a potential strategy to improve cancer immunotherapy

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