HIF-1α inhibition promotes the efficacy of immune checkpoint blockade in the treatment of non-small cell lung cancer

Luo, Fan; Lü, Fangli; Cao, Jia-Xin; Ma, Wenjuan; Xia, Zengfei; Zhan, Jie; Zeng, Kangmei; Huang, Yan; Zhao, Hongyun; Zhang, Li

doi:10.1016/j.canlet.2022.01.027

Cited by 41 publications

(36 citation statements)

References 54 publications

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“…Experimental studies support this hypothesis. Luo et al showed that treating mice bearing a syngeneic lung carcinoma with PX-478 (a selective HIF1α inhibitor) resulted in increased intratumoral accumulation of granzyme B secreting TILs, which prolonged the survival of mice treated with immunotherapy [ 35 ]. Jayaprakash et al demonstrated that the hypoxia-activated prodrug TH-302 reduces hypoxia in spontaneous prostate cancer tumors and drives influx of T-cells, enhancing the efficacy of anti CTLA4/PD-L1 immunotherapy [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Prognostic and Predictive Relevance of Tumor-Infiltrating Lymphocytes in Squamous Cell Head–Neck Cancer Patients Treated with Radical Radiotherapy/Chemo-Radiotherapy

et al. 2022

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Microenvironmental conditions control the entrance and thriving of cytotoxic lymphocytes in tumors, allowing or preventing immune-mediated cancer cell death. We investigated the role of tumor-infiltrating lymphocyte (TIL) density in the outcome of radiotherapy in a series of squamous cell head–neck tumors (HNSCC). Moreover, we assessed the link between markers of hypoxia and TIL density. One-hundred twenty-one patients with HNSCC treated prospectively with radical radiotherapy/chemo-radiotherapy were analyzed. The assessment of TIL density was performed on hematoxylin and eosin biopsy sections before radiotherapy. TIL density ranged from 0.8 to 150 lymphocytes per ×40 optical field (median 27.5). Using the median value, patients were grouped into two categories of low and high TIL density. Early T-stage tumors had a significantly higher TIL density (p < 0.003), but we found no association with N-stage. Overexpression of HIF1α, HIF2α, and CA9 was significantly linked with poor infiltration by TILs (p < 0.03). A significant association of high TIL density with better disease-specific overall survival and improved locoregional relapse-free survival was noted (p = 0.008 and 0.02, respectively), which was also confirmed in multivariate analysis. It is concluded that HNSCC phenotypes that allow for the intratumoral accumulation of lymphocytes have a better outcome following radical radiotherapy/chemo-radiotherapy. Intratumoral-activated HIF- and CA9-related pathways characterize immunologically cold tumors and may be used as targets for therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Prognostic and Predictive Relevance of Tumor-Infiltrating Lymphocytes in Squamous Cell Head–Neck Cancer Patients Treated with Radical Radiotherapy/Chemo-Radiotherapy

et al. 2022

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“…PX-478 has been shown to effectively downregulate both HIF-1α and PD-L1 in experimental glioma cells [82]. As mentioned before, a combination of PX-478 with anti-PD-1 antibody effectively suppressed the growth of murine tumors and prolonged the survival of host mice [86]. Figure 5B shows that PX-478 delayed the growth of FSaII tumors and significantly enhanced the effect of radiation to suppress the tumor growth, which may be attributed, in part, to the suppression of the HIF-1α/PD-L1 pathway.…”

Section: Suppression Of Pd-l1 Expression With Hif-1α Inhibitorsmentioning

confidence: 80%

“…Furthermore, the HIF-1α inhibition with echinomycin synergistically increased the immunotherapeutic effects of anti-CTLA-4 antibodies in mouse tumor models [85]. It has also been reported that inhibition of HIF-1α with PX-478, an experimental HIF-1α inhibitor, synergized with anti-PD-1 antibodies to suppress the growth of murine tumors and prolonged the survival of host mice [86]. Taken together, it is highly likely that a combination of HIF-1α inhibitors with immune checkpoint inhibitors would significantly improve anti-tumor immunity [69].…”

Section: Suppression Of Pd-l1 Expression With Hif-1α Inhibitorsmentioning

confidence: 89%

HIF-1α Inhibition Improves Anti-Tumor Immunity and Promotes the Efficacy of Stereotactic Ablative Radiotherapy (SABR)

Song

Kim

Cho

et al. 2022

Cancers

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High-dose hypofractionated radiation such as SABR (stereotactic ablative radiotherapy) evokes an anti-tumor immune response by promoting a series of immune-stimulating processes, including the release of tumor-specific antigens from damaged tumor cells and the final effector phase of immune-mediated lysis of target tumor cells. High-dose hypofractionated radiation also causes vascular damage in tumors, thereby increasing tumor hypoxia and upregulation of hypoxia-inducible factors HIF-1α and HIF-2α, the master transcription factors for the cellular response to hypoxia. HIF-1α and HIF-2α are critical factors in the upregulation of immune suppression and are the master regulators of immune evasion of tumors. Consequently, SABR-induced increase in anti-tumor immunity is counterbalanced by the increase in immune suppression mediated by HIFα. Inhibition of HIF-1α with small molecules such as metformin downregulates immunosuppressive pathways, including the expression of immune checkpoints, and it improves or restores the anti-tumor immunity stimulated by irradiation. Combinations of HIFα inhibitors, particularly HIF-1α inhibitors, with immune checkpoint blocking antibodies may represent a novel approach to boost the overall anti-tumor immune profile in patients and thus enhance outcomes after SABR.

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“…There are several HIF‐1 inhibitors and clinical trials that have been reviewed elsewhere 159,160 . While space constraints limit our discussion on the topic, preclinical studies indicate that combining HIF inhibition with immune checkpoint inhibitors can promote anti‐tumour immunity in various cancers 161,162 . Moreover, drugs including PX‐478, bortezomib and chetomin that could indirectly inhibit HIF‐1 protein expression have demonstrated radiosensitization in several cancers at preclinical level 163–167 .…”

Section: Targeting Tumour Hypoxia To Overcome Resistance To Radiother...mentioning

confidence: 99%

“…159,160 While space constraints limit our discussion on the topic, preclinical studies indicate that combining HIF inhibition with immune checkpoint inhibitors can promote anti-tumour immunity in various cancers. 161,162 Moreover, drugs including PX-478, bortezomib and chetomin that could indirectly inhibit HIF-1 protein expression have demonstrated radiosensitization in several cancers at preclinical level. [163][164][165][166][167] Combinations of HIF inhibitors, radiotherapy and PD-1/PD-L1 blockade is a growing area of interest, and further studies will determine whether this is a viable strategy.…”

Section: Inhibiting Hif Activitymentioning

confidence: 99%

Improving the synergistic combination of programmed death‐1/programmed death ligand‐1 blockade and radiotherapy by targeting the hypoxic tumour microenvironment

et al. 2022

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Immune checkpoint inhibition with PD-1/PD-L1 blockade is a promising area in the field of anti-cancer therapy. Although clinical data have revealed success of PD-1/PD-L1 blockade as monotherapy or in combination with CTLA-4 or chemotherapy, the combination with radiotherapy could further boost antitumour immunity and enhance clinical outcomes due to the immunostimulatory effects of radiation. However, the synergistic combination of PD-1/PD-L1 blockade and radiotherapy can be challenged by the complex nature of the tumour microenvironment (TME), including the presence of tumour hypoxia. Hypoxia is a major barrier to the effectiveness of both radiotherapy and PD-1/ PD-L1 blockade immunotherapy. Thus, targeting the hypoxic TME is an attractive strategy to enhance the efficacy of the combination. Addition of compounds that directly or indirectly reduce hypoxia, to the combination of PD-1/ PD-L1 inhibitors and radiotherapy may optimize the success of the combination and improve therapeutic outcomes. In this review, we will discuss the synergistic combination of PD-1/PD-L1 blockade and radiotherapy and highlight the role of hypoxic TME in impeding the success of both therapies. In addition, we will address the potential approaches for targeting tumour hypoxia and how exploiting these strategies could benefit the combination of PD-1/PD-L1 blockade and radiotherapy.

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HIF-1α inhibition promotes the efficacy of immune checkpoint blockade in the treatment of non-small cell lung cancer

Cited by 41 publications

References 54 publications

Prognostic and Predictive Relevance of Tumor-Infiltrating Lymphocytes in Squamous Cell Head–Neck Cancer Patients Treated with Radical Radiotherapy/Chemo-Radiotherapy

Prognostic and Predictive Relevance of Tumor-Infiltrating Lymphocytes in Squamous Cell Head–Neck Cancer Patients Treated with Radical Radiotherapy/Chemo-Radiotherapy

HIF-1α Inhibition Improves Anti-Tumor Immunity and Promotes the Efficacy of Stereotactic Ablative Radiotherapy (SABR)

Improving the synergistic combination of programmed death‐1/programmed death ligand‐1 blockade and radiotherapy by targeting the hypoxic tumour microenvironment

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