Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade

Dai, Xiaoming; Bu, Xia; Gao, Yang; Guo, Jianping; Hu, Jia; Jiang, Cong; Zhang, Zhao; Xu, Kexin; Duan, Jinzhi; He, Shaohui; Zhang, Jinfang; Wan, Lixin; Liu, Tianjie; Zhou, Xiaobo; Hung, Mien Chie; Freeman, Gordon J.

doi:10.1016/j.molcel.2021.03.037

Cited by 126 publications

(99 citation statements)

References 83 publications

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“…While the impact of obesity in BC patients remains complex and unresolved [ 76 ], the dietary restriction schedules gain some attention as they can switch the metabolic reprogramming within cancer cells that can boost the outcome of the immunotherapy. It was shown that ketogenic stress or AMPK agonists acting via AMPK pathway decrease PD-L1 abundance, enhance antigen presentation and in the end increase the efficacy of anti-CTLA-4 immunotherapy [ 77 ]. It was also shown that a ketogenic diet induces changes in the composition of microbiota that result in an increase of 3-hydroxybutyrate (3HB) in serum.…”

Section: Immune Landscape Of Breast Cancersmentioning

confidence: 99%

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

Retecki

Seweryn

Graczyk-Jarzynka

et al. 2021

Cancers

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Breast cancer (BC) has traditionally been considered to be not inherently immunogenic and insufficiently represented by immune cell infiltrates. Therefore, for a long time, it was thought that the immunotherapies targeting this type of cancer and its microenvironment were not justified and would not bring benefits for breast cancer patients. Nevertheless, to date, a considerable number of reports have indicated tumor-infiltrating lymphocytes (TILs) as a prognostic and clinically relevant biomarker in breast cancer. A high TILs expression has been demonstrated in primary tumors, of both, HER2-positive BC and triple-negative (TNBC), of patients before treatment, as well as after treatment with adjuvant and neoadjuvant chemotherapy. Another milestone was reached in advanced TNBC immunotherapy with the help of the immune checkpoint inhibitors directed against the PD-L1 molecule. Although those findings, together with the recent developments in chimeric antigen receptor T cell therapies, show immense promise for significant advancements in breast cancer treatments, there are still various obstacles to the optimal activity of immunotherapeutics in BC treatment. Of these, the immunosuppressive tumor microenvironment constitutes a key barrier that greatly hinders the success of immunotherapies in the most aggressive types of breast cancer, HER2-positive and TNBC. Therefore, the improvement of the current and the demand for the development of new immunotherapeutic strategies is strongly warranted.

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Section: Immune Landscape Of Breast Cancersmentioning

confidence: 99%

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

Retecki

Seweryn

Graczyk-Jarzynka

et al. 2021

Cancers

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“…The protein level expression of PD-L1 in cancer cells seems to be regulated by various factors ( Figure 4 ). PD-L1 protein levels (but not mRNA) were downregulated in human and mouse cancer cells subjected to glucose starvation which was linked to activation of AMPK ( Figure 4 A) [ 97 ]. Furthermore, AMPK phosphorylation of PD-L1 results in its degradation by autophagy.…”

Section: Metabolic Effects Of Immune Checkpoint Protein Activation On Cancer Cellsmentioning

confidence: 99%

“…Furthermore, AMPK phosphorylation of PD-L1 results in its degradation by autophagy. In the same study, inhibition of glycolysis with 2-DG resulted in the activation of AMPK and downregulation of PD-L1 [ 97 ].…”

Section: Metabolic Effects Of Immune Checkpoint Protein Activation On Cancer Cellsmentioning

confidence: 99%

“…Other studies have found that the ketogenic diet was associated with downregulated PD-L1 protein levels in a murine model of colorectal cancer. In vitro experiments in low-glucose culture media supplemented with the ketone, body β-hydroxybutyrate demonstrated that the changes in PD-L1 expression were not regulated by ketone body supplementation but were due to the low levels of glucose in media [ 97 ]. Furthermore, the mechanism for PD-L1 downregulation was mediated by AMPK phosphorylation of PD-L1 and subsequent degradation by autophagy [ 97 ].…”

Section: Impact Of Diet and The Microbiome On Immune Checkpoint Blockade Responsementioning

confidence: 99%

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Metabolic Implications of Immune Checkpoint Proteins in Cancer

Stirling

Bronson

Mackert

et al. 2022

Cells

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Expression of immune checkpoint proteins restrict immunosurveillance in the tumor microenvironment; thus, FDA-approved checkpoint inhibitor drugs, specifically PD-1/PD-L1 and CTLA-4 inhibitors, promote a cytotoxic antitumor immune response. Aside from inflammatory signaling, immune checkpoint proteins invoke metabolic reprogramming that affects immune cell function, autonomous cancer cell bioenergetics, and patient response. Therefore, this review will focus on the metabolic alterations in immune and cancer cells regulated by currently approved immune checkpoint target proteins and the effect of costimulatory receptor signaling on immunometabolism. Additionally, we explore how diet and the microbiome impact immune checkpoint blockade therapy response. The metabolic reprogramming caused by targeting these proteins is essential in understanding immune-related adverse events and therapeutic resistance. This can provide valuable information for potential biomarkers or combination therapy strategies targeting metabolic pathways with immune checkpoint blockade to enhance patient response.

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“…The blockage of MYCN or specific MYCN dependencies could ameliorate the immune suppression by restoring the responsiveness of the immune system, opening the way to combinatorial treatments with immunotherapies. In this context, the link between MYCN and polycomb repressive complex 2 (PRC2) may offer a promising therapeutic opportunity via a mechanism that alters TME immunogenicity (198,199).…”

Section: Immunotherapy In Medulloblastomamentioning

confidence: 99%

Biological Role of MYCN in Medulloblastoma: Novel Therapeutic Opportunities and Challenges Ahead

et al. 2021

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The constitutive and dysregulated expression of the transcription factor MYCN has a central role in the pathogenesis of the paediatric brain tumour medulloblastoma, with an increased expression of this oncogene correlating with a worse prognosis. Consequently, the genomic and functional alterations of MYCN represent a major therapeutic target to attenuate tumour growth in medulloblastoma. This review will provide a comprehensive synopsis of the biological role of MYCN and its family components, their interaction with distinct signalling pathways, and the implications of this network in medulloblastoma development. We will then summarise the current toolbox for targeting MYCN and highlight novel therapeutic avenues that have the potential to results in better-tailored clinical treatments.

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Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade

Cited by 126 publications

References 83 publications

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

Metabolic Implications of Immune Checkpoint Proteins in Cancer

Biological Role of MYCN in Medulloblastoma: Novel Therapeutic Opportunities and Challenges Ahead

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