Inhibition of mTOR complex 1/p70 S6 kinase signaling elevates PD-L1 levels in human cancer cells through enhancing protein stabilization accompanied with enhanced β-TrCP degradation

Deng, Liang; Qian, Guoqing; Zhang, Shuo; Zheng, Hongmei; Fan, Sonqing; Lesinski, Gregory B.; Owonikoko, Taofeek K.; Ramalingam, Suresh S.; Sun, Shi‐Yong

doi:10.1038/s41388-019-0877-4

Cited by 64 publications

(63 citation statements)

References 56 publications

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“…The high expression of PD-L1 protein levels is observed in different types of cancers, which promotes cancer cell immune escape 5,7 . The expression of PD-L1 in cancer cells is regulated by multiple signaling pathways, including NFκB, MAPK, mTOR, STAT, and c-Myc 8,9 , while PD-L1 protein undergoes degradation in proteasomes or lysosomes by multiple pathways [10][11][12][13][14][15][16] , leading to increased effectiveness of cancer immunotherapy (Figs. 1 and 2 and Tables 1 and 2).…”

Section: Introductionmentioning

confidence: 99%

PD-L1 degradation pathway and immunotherapy for cancer

et al. 2020

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Programmed death ligand 1 (PD-L1, CD274) is an essential immune checkpoint protein that binds to programmed death 1 (PD-1) on T-lymphocytes. T cell plays a critical role in killing cancer cells while the cancer cell exhibits immune escape by the expression of PD-L1. The binding of PD-L1 to PD-1 inhibits T cell proliferation and activity, leading to tumor immunosuppression. Increasing evidence shows that PD-L1 protein undergoes degradation in proteasomes or lysosomes by multiple pathways, leading to enhanced immunotherapy for cancer. Although some specific drugs induce PD-L1 degradation and increase antitumor activity, the combination of these drugs with PD-L1/PD-1 blockade significantly enhances cancer immunotherapy. In this review, we have discussed the interaction of PD-L1 degradation with cancer immunotherapy.

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Section: Introductionmentioning

confidence: 99%

PD-L1 degradation pathway and immunotherapy for cancer

et al. 2020

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“…Lastwika et al show that PD-L1 is tightly regulated by the Akt-mTOR pathway, where activation can lead to immune escape for some tumor types 53 . Previous inhibition studies confirmed that the control of PD-L1 is PI3k/Akt/mTOR specific via mTORC1 (pAKT) and mTORC2 (pS6) signaling 53,54 . Thus, we studied the key PI3k/Akt/mTOR constituents in pAkt and RPS6, ribosomal protein S6, to confirm the downstream impact on PD-L1.…”

Section: Chemerin Inhibits Pakt and Ps6 Signaling Leading To Decreasementioning

confidence: 84%

Chemerin increases T-cell mediated cytotoxicity of human tumors via modulation of a novel CMKLR1/PTEN/PD-L1 axis

Rennier

Krug

Virdi

et al. 2019

Preprint

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Chemerin (RARRES2) is an endogenous leukocyte chemoattractant known to recruit innate immune cells through its chemotactic receptor, CMKLR1. RARRES2 is often downregulated in prostate cancer and across multiple tumor types compared to normal tissue. Additionally, a methylome-wide analysis identified RARRES2 as one of the most hypermethylated genes in sarcoma. Recent studies have shown that augmenting chemerin in the tumor microenvironment significantly suppresses tumor growth, at least in part by recruitment of immune effector cells. However, as tumor cells have been shown to express functional chemokine receptors that can impact their phenotype, we hypothesized that chemerin might have additional, tumor-intrinsic effects. Here, we show for the first time that human cancer cells exposed to exogenous chemerin significantly upregulate PTEN expression and activity. Additionally, chemerin-induced PTEN expression correlated with a concomitant reduction in PD-L1 mRNA and protein expression. Chemerin treatment of tumor cells led to significantly reduced tumor cell migration/invasion, as well as significantly increased cytotoxicity by T cells. siRNA knockdown of tumor expressed CMKLR1 abrogated chemerin-induced modulation of PTEN and PD-L1 expression and activity, supporting the presence of a CMKLR1/PTEN/PD-L1 signaling cascade. We then compared chemerin treatment to PD-L1 inhibition by siRNA knockdown or the antagonistic antibody atezolizumab in T cell cytotoxicity assays and surprisingly found chemerin treatment was as effective as both Chemerin modulates PTEN/PD-L1 via CMKLR1 in human tumors Page 2 of 29 PD-L1 knockdown and atezolizumab treatment in mediating tumor lysis. Collectively, our data show a novel link between chemerin, PTEN and PD-L1 in human tumor lines, with functional consequences that may have a role in improving T cell-mediated immunotherapies. Runnning Title: Chemerin modulates PTEN/PD-L1 via CMKLR1 in human tumors Word Counts: Abstract -250

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“…In contrast, in several mutant EGFR (EGFR L858R/T790M ) and KRas (KRas LA2 and KRas G12D ) murine lung cancer models, active AKT-mTOR signaling actually increases PD-L1 expression [42]. Therefore, the impact of particular signalling pathways such as mTORC1 (and thus upstream PI 3-kinase signalling) on PD-L1 expression differs substantially between types of cancers or cancer cells [40][41][42].…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of mTORC1 and its substrate S6K, both of which are negative regulators of eEF2K [38,39], has also been shown to promote the synthesis of PD-L1 in lung cancer cells [40], although in that case this was attributed to effects on the stability of the PD-L1 protein. Furthermore, the mTOR inhibitor everolimus also increases PD-L1 expression in renal cell carcinoma lines [41], an effect which, at least in part, might involve the activation of eEF2K.…”

Section: Discussionmentioning

confidence: 99%

eEF2 kinase enhances the expression of PD-L1 by promoting the translation of its mRNA

Xie

Jin

et al. 2020

Preprint

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Emerging advances in cancer therapy have transformed the landscape from conventional therapies towards cancer immunotherapy regimens. Recent discoveries have resulted in the development of clinical immune checkpoint inhibitors that are ‘game-changers’ for cancer immunotherapy. Here we show that eEF2K, an atypical protein kinase that inhibits the elongation stage of protein synthesis, actually promotes the synthesis of PD-L1, an immune checkpoint protein which helps cancer cells to escape from immunosurveillance. Ablation of eEF2K in prostate and lung cancer cells markedly reduced the expression levels of the PD-L1 protein. We show that eEF2K promotes the association of PD-L1 mRNAs with translationally active polyribosomes and that translation of the PD-L1 mRNA is regulated by a uORF (upstream open reading-frame) within its 5’-UTR (5’-untranslated region) which starts with a non-canonical CUG codon. This inhibitory effect is attenuated by eEF2K thereby allowing higher levels of translation of the PD-L1 coding region and enhanced expression of the PD-L1 protein. Moreover, eEF2K-depleted cancer cells are more vulnerable to immune attack by natural killer cells. Therefore, control of translation elongation can modulate the translation of this specific mRNA, one which contains an uORF that starts with CUG, and perhaps others that contain a similar feature. Taken together, our data reveal that eEF2K regulates PD-L1 expression at the level of the translation of its mRNA by virtue of a uORF in its 5’-region. This, and other roles of eEF2K in cancer cell biology (e.g., in cell survival and migration), may be exploited for the design of future therapeutic strategies.

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Inhibition of mTOR complex 1/p70 S6 kinase signaling elevates PD-L1 levels in human cancer cells through enhancing protein stabilization accompanied with enhanced β-TrCP degradation

Cited by 64 publications

References 56 publications

PD-L1 degradation pathway and immunotherapy for cancer

PD-L1 degradation pathway and immunotherapy for cancer

Chemerin increases T-cell mediated cytotoxicity of human tumors via modulation of a novel CMKLR1/PTEN/PD-L1 axis

eEF2 kinase enhances the expression of PD-L1 by promoting the translation of its mRNA

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