1,979
Views
2
CrossRef citations to date
0
Altmetric
Research Paper

Everolimus (RAD001) combined with programmed death-1 (PD-1) blockade enhances radiosensitivity of cervical cancer and programmed death-ligand 1 (PD-L1) expression by blocking the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) pathway

, &
Pages 11240-11257 | Received 10 Jan 2022, Accepted 05 Apr 2022, Published online: 29 Apr 2022

References

  • Park SH, Kim M, Lee S, et al. Therapeutic potential of natural products in treatment of cervical cancer: a review. Nutrients. 2021;13: 154. https://doi.org/10.6084/m9.figshare.19626009
  • Francies FZ, Bassa S, Chatziioannou A, et al. Splicing genomics events in cervical cancer: insights for phenotypic stratification and biomarker potency. Genes (Basel). 2021;12(2):130.
  • Kagabu M, Nagasawa T, Sato C, et al. Immunotherapy for uterine cervical cancer using checkpoint Inhibitors: future directions. Int J Mol Sci. 2020;21(7):2335.
  • Tapera O, Nyakabau AM, Simango N, et al. Gaps and opportunities for cervical cancer prevention, diagnosis, treatment and care: evidence from midterm review of the Zimbabwe cervical Cancer prevention and control strategy (2016-2020). BMC Public Health. 2021;21(1):1478.
  • Rossman AH, Reid HW, Pieters MM, et al. Digital Health strategies for cervical cancer control in low- and middle-income Countries: systematic review of current implementations and gaps in research. J Med Internet Res. 2021;23(5):e23350.
  • Marima R, Hull R, Lolas G, et al. The Catastrophic HPV/HIV dual viral oncogenomics in concert with dysregulated alternative splicing in cervical cancer. Int J Mol Sci. 2021;22(18):10115.
  • Kramer J. Eradicating cervical cancer: lessons learned from Rwanda and Australia. Int J Gynaecol Obstet. 2021;154(2):270–276.
  • Kim JY, Byun SJ, Kim YS, et al. Disease courses in patients with residual tumor following concurrent chemoradiotherapy for locally advanced cervical cancer. Gynecol Oncol. 2017;144(1):34–39.
  • Nanthamongkolkul K, Hanprasertpong J. Predictive Factors of Pelvic Lymph Node Metastasis in Early-Stage Cervical Cancer. Oncol Res Treat. 2018;41(4):194–198.
  • Waggoner SE. Cervical cancer. Lancet. 2003;361(9376):2217–2225.
  • Lecavalier-Barsoum M, Chaudary N, Han K, et al. Targeting the CXCL12/CXCR4 pathway and myeloid cells to improve radiation treatment of locally advanced cervical cancer. Int J Cancer. 2018;143(5):1017–1028.
  • Jiao X, Zhang S, Jiao J, et al. Promoter methylation of SEPT9 as a potential biomarker for early detection of cervical cancer and its overexpression predicts radioresistance. Clin Epigenetics. 2019;11(1):120.
  • Rashidi S, Mansouri R, Ali-Hassanzadeh M, et al. The host mTOR pathway and parasitic diseases pathogenesis. Parasitol Res. 2021;120(4):1151–1166.
  • Ji J, Zheng P-S. Activation of mTOR signaling pathway contributes to survival of cervical cancer cells. Gynecol Oncol. 2010;117(1):103–108.
  • Zhu W, Fu W, Hu L. NVP-BEZ235, dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, prominently enhances radiosensitivity of prostate cancer cell line PC-3. Cancer Biother Radiopharm. 2013;28(9):665–673.
  • Choi J, Yoon YN, Kim N, et al. Predicting radiation resistance in breast cancer with expression status of phosphorylated S6K1. Sci Rep. 2020;10(1):641.
  • Tian T, Li X, Zhang J. mTOR signaling in cancer and mTOR inhibitors in solid tumor targeting therapy. Int J Mol Sci. 2019;755.
  • Assad DX, Borges GA, Avelino SR, et al. Additive cytotoxic effects of radiation and mTOR inhibitors in a cervical cancer cell line. Pathol Res Pract. 2018;214(2):259–262.
  • Chao A, Lin CY, Wu RC, et al. The combination of everolimus and terameprocol exerts synergistic antiproliferative effects in endometrial cancer: molecular role of insulin-like growth factor binding protein 2. J Mol Med (Berl). 2018;96(11):1251–1266.
  • Kim SJ, Shin DY, Kim JS, et al. A phase II study of everolimus (RAD001), an mTOR inhibitor plus CHOP for newly diagnosed peripheral T-cell lymphomas. Ann Oncol. 2016;27(4):712–718.
  • Gao F, Li R, Wei PF, et al. Synergistic anticancer effects of everolimus (RAD001) and Rhein on gastric cancer cells via phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. Bioengineered. 2022;13(3):6332–6342.
  • Chen Y, Pei Y, Luo J, et al. Looking for the Optimal PD-1/PD-L1 inhibitor in cancer treatment: a comparison in basic structure, function, and clinical practice. Front Immunol. 2020;11:1088.
  • Howitt BE, Sun HH, Roemer MG, et al. Genetic basis for PD-L1 expression in squamous cell carcinomas of the cervix and vulva. JAMA Oncol. 2016;2(4):518–522.
  • Frenel JS, Le Tourneau C, O’Neil B, et al. Safety and Efficacy of pembrolizumab in advanced, programmed death ligand 1-Positive cervical cancer: results from the phase Ib KEYNOTE-028 Trial. J Clin Oncol. 2017;35(36):4035–4041.
  • Sasaki A, Nakamura Y, Togashi Y, et al. Enhanced tumor response to radiotherapy after PD-1 blockade in metastatic gastric cancer. Gastric Cancer. 2020;23(5):893–903.
  • Jiang K, Zou H. microRNA-20b-5p overexpression combing Pembrolizumab potentiates cancer cells to radiation therapy via repressing programmed death-ligand 1. Bioengineered. 2022;13(1):917–929.
  • Zhu L, Zhao Y, Yu L, et al. Overexpression of ADAM9 decreases radiosensitivity of hepatocellular carcinoma cell by activating autophagy. Bioengineered. 2021;12(1):5516–5528.
  • Hirayama Y, Gi M, Yamano S, et al. Anti-PD-L1 treatment enhances antitumor effect of everolimus in a mouse model of renal cell carcinoma. Cancer Science. 2016;107(12):1736–1744.
  • Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–1813.
  • Dent P, Booth L, Poklepovic A, et al. Signaling alterations caused by drugs and autophagy. Cell Signal. 2019;64:109416.
  • Robainas M, Otano R, Bueno S, et al. Understanding the role of PD-L1/PD1 pathway blockade and autophagy in cancer therapy. Onco Targets Ther. 2017;10:1803–1807.
  • Xia C, He Z, Cai Y. Quantitative proteomics analysis of differentially expressed proteins induced by astragaloside IV in cervical cancer cell invasion. Cell Mol Biol Lett. 2020;25(1):25.
  • Yadollahi P, Jeon YK, Ng WL, et al. Current understanding of cancer-intrinsic PD-L1: regulation of expression and its protumoral activity. BMB Rep. 2021;54(1):12–20.
  • Lin JF, Lin YC, Yang SC, et al. Autophagy inhibition enhances RAD001-induced cytotoxicity in human bladder cancer cells. Drug Des Devel Ther. 2016;10:1501–1513.
  • Liao J, Jin H, Li S, et al. Apatinib potentiates irradiation effect via suppressing PI3K/AKT signaling pathway in hepatocellular carcinoma. J Exp Clin Cancer Res. 2019;38(1):454.
  • He Y, Jing Y, Wei F, et al. Long non-coding RNA PVT1 predicts poor prognosis and induces radioresistance by regulating DNA repair and cell apoptosis in nasopharyngeal carcinoma. Cell Death Dis. 2018;9(2):235.
  • Shiratori H, Kawai K, Hata K, et al. The combination of temsirolimus and chloroquine increases radiosensitivity in colorectal cancer cells. Oncol Rep. 2019;42(1):377–385.
  • Cai Y, Xia Q, Su Q, et al. mTOR inhibitor RAD001 (everolimus) induces apoptotic, not autophagic cell death, in human nasopharyngeal carcinoma cells. Int J Mol Med. 2013;31(4):904–912.
  • Luo H, Yu YY, Chen HM, et al. The combination of NVP-BEZ235 and rapamycin regulates nasopharyngeal carcinoma cell viability and apoptosis via the PI3K/AKT/mTOR pathway. Exp Ther Med. 2019;17(1):99–106.
  • Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–408.
  • Qu QX, Xie F, Huang Q, et al. Membranous and cytoplasmic expression of PD-L1 in ovarian cancer cells. Cell Physiol Biochem. 2017;43(5):1893–1906.
  • Ye C, Sun NX, Ma Y, et al. MicroRNA-145 contributes to enhancing radiosensitivity of cervical cancer cells. FEBS Lett. 2015;589(6):702–709.
  • Ames IH, Gagne GM, Garcia AM, et al. Preferential homing of tumor-infiltrating lymphocytes in tumor-bearing mice. Cancer Immunol Immunother. 1989;29(2):93–100.
  • Albert JM, Kim KW, Cao C, et al. Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer. Mol Cancer Ther. 2006;5(5):1183–1189.
  • Chen H, Ma Z, Vanderwaal RP, et al. The mTOR inhibitor rapamycin suppresses DNA double-strand break repair. Radiat Res. 2021;175(2):214–224.
  • Kim KW, Myers CJ, Jung DK, et al. NVP-BEZ-235 enhances radiosensitization via blockade of the PI3K/mTOR pathway in cisplatin-resistant non-small cell lung carcinoma. Genes Cancer. 2014;5(7–8):293–302.
  • Du C, Li DQ, Li N, et al. DDX5 promotes gastric cancer cell proliferation in vitro and in vivo through mTOR signaling pathway. Sci Rep. 2017;7(1):42876.
  • Klionsky, DJ, Abdalla, FC, Abeliovich, Het al, Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2012;8:445–544
  • Ichimura Y, Kominami E, Tanaka K, et al. Selective turnover of p62/A170/SQSTM1 by autophagy. Autophagy. 2008;4(8):1063–1066.
  • Wang X, Wkk W, Gao J, et al. Autophagy inhibition enhances PD-L1 expression in gastric cancer. J Exp Clin Cancer Res. 2019;38(1):140.
  • Castle PE, Einstein MH, Sahasrabuddhe VV. Cervical cancer prevention and control in women living with human immunodeficiency virus. CA Cancer J Clin. 2021;71(6):505–526.
  • Hata M. Radiation therapy for elderly patients with uterine cervical cancer: feasibility of curative treatment. Int J Gynecol Cancer. 2019;29(3):622–629.
  • Prabakaran DS, Muthusami S, Sivaraman T, et al. Silencing of FTS increases radiosensitivity by blocking radiation-induced Notch1 activation and spheroid formation in cervical cancer cells. Int J Biol Macromol. 2019;126:1318–1325.
  • Wu Y, Huang J, Xu H, et al. Over-expression of miR-15a-3p enhances the radiosensitivity of cervical cancer by targeting tumor protein D52. Biomed Pharmacother. 2018;105:1325–1334.
  • Chen YH, Wu JX, Yang SF, et al. Metformin potentiates the anticancer effect of everolimus on cervical cancer in vitro and in vivo. Cancers (Basel). 2021;14(1):13.
  • Rischin D, Gil-Martin M, Gonzalez-Martin A, et al. PD-1 blockade in recurrent or metastatic cervical cancer: data from cemiplimab phase I expansion cohorts and characterization of PD-L1 expression in cervical cancer. Gynecol Oncol. 2020;159(2):322–328.
  • Bamodu OA, Chang HL, Ong JR, et al. Elevated PDK1 Expression Drives PI3K/AKT/MTOR signaling promotes radiation-resistant and dedifferentiated phenotype of hepatocellular Carcinoma. Cells. 2020;9:746.
  • Jeon YJ, Yi SA, Lee J, et al. Nuclear S6K1 regulates cAMP-responsive element-dependent gene transcription through activation of mTOR signal pathway. Biochem Biophys Res Commun. 2022;594:101–108.
  • Gao S, Li E, Gao H. Long non-coding RNA MEG3 attends to morphine-mediated autophagy of HT22 cells through modulating ERK pathway. Pharm Biol. 2019;57(1):536–542.
  • Wang F, Zhang H, Lu X, et al. Chlamydia trachomatis induces autophagy by p62 in HeLa cell. World J Microbiol Biotechnol. 2021;37(3):50.
  • Marquard FE, Jucker M. PI3K/AKT/mTOR signaling as a molecular target in head and neck cancer. Biochem Pharmacol. 2020;172:113729.
  • Schwarz JK, Payton JE, Rashmi R, et al. Pathway-specific analysis of gene expression data identifies the PI3K/Akt pathway as a novel therapeutic target in cervical cancer. Clin Cancer Res. 2012;18(5):1464–1471.
  • Kim MJ, Min Y, Im JS, et al. p62 is Negatively Implicated in the TRAF6-BECN1 Signaling Axis for Autophagy Activation and Cancer Progression by Toll-Like Receptor 4 (TLR4). Cells. 2020;9:1142.
  • Cui C, Li Z, Wu D. The long non-coding RNA H19 induces hypoxia/reoxygenation injury by up-regulating autophagy in the hepatoma carcinoma cells. Biol Res. 2019;52(1):32.
  • Chen H, Chen N, Li F, et al. Repeated radon exposure induced lung injury and epithelial-mesenchymal transition through the PI3K/AKT/mTOR pathway in human bronchial epithelial cells and mice. Toxicol Lett. 2020;334:4–13.
  • Sun Y, Chen K, Lin G, et al. Silencing c-Jun inhibits autophagy and abrogates radioresistance in nasopharyngeal carcinoma by activating the PI3K/AKT/mTOR pathway. Ann Transl Med. 2021;9(13):1085.
  • Ye Z, Xie T, Yan F, et al. MiR-34a reverses radiation resistance on ECA-109 cells by inhibiting PI3K/AKT/mTOR signal pathway through downregulating the expression of SIRT1. Int J Radiat Biol. 2021;97(4):452–463.
  • Cui J, Guo Y, Wu H, et al. Everolimus regulates the activity of gemcitabine-resistant pancreatic cancer cells by targeting the Warburg effect via PI3K/AKT/mTOR signaling. Mol Med. 2021;27(1):38.
  • Lee MW, Kim DS, Eom J-E, et al. RAD001 (everolimus) enhances TRAIL cytotoxicity in human leukemic Jurkat T cells by upregulating DR5. Biochem Biophys Res Commun. 2015;463(4):894–899.
  • Liu Y, Zhang Z, Yan L, et al. Everolimus reduces postoperative arthrofibrosis in rabbits by inducing autophagy-mediated fibroblast apoptosis by PI3K/Akt/mTOR signaling pathway. Biochem Biophys Res Commun. 2020;533(1):1–8.
  • Huang XY, Hu QP, Shi HY, et al. Everolimus inhibits PI3K/Akt/mTOR and NF-kB/IL-6 signaling and protects seizure-induced brain injury in rats. J Chem Neuroanat. 2021;114:101960.
  • Xu G, Yan X, Hu Z, et al. Glucocappasalin Induces G2/M-Phase Arrest, apoptosis, and autophagy pathways by targeting CDK1 and PLK1 in cervical carcinoma cells. Front Pharmacol. 2021;12:671138.
  • Mardanshahi A, Gharibkandi NA, Vaseghi S, et al. The PI3K/AKT/mTOR signaling pathway inhibitors enhance radiosensitivity in cancer cell lines. Mol Biol Rep. 2021;48(8):1–14.
  • Naruse T, Yanamoto S, Yamada S, et al. Anti-tumor effect of the mammalian target of rapamycin inhibitor everolimus in oral squamous cell carcinoma. Pathol Oncol Res. 2015;21(3):765–773.
  • Liu S, Zang H, Zheng H, et al. miR-4634 augments the anti-tumor effects of RAD001 and associates well with clinical prognosis of non-small cell lung cancer. Sci Rep. 2020;10(1):13079.
  • Dong P, Hao F, Dai S, et al. Combination therapy Eve and Pac to induce apoptosis in cervical cancer cells by targeting PI3K/AKT/mTOR pathways. J Recept Signal Transduct Res. 2018;38(1):83–88.
  • Kirova YM, Servois V, Chargari C, et al. Further developments for improving response and tolerance to irradiation for advanced renal cancer: concurrent (mTOR) inhibitor RAD001 and helical tomotherapy. Invest New Drugs. 2012;30(3):1241–1243.
  • Yu CC, Hung SK, Liao HF, et al. RAD001 enhances the radiosensitivity of SCC4 oral cancer cells by inducing cell cycle arrest at the G2/M checkpoint. Anticancer Res. 2014;34(6):2927–2935.
  • Kuwahara Y, Mori M, Kitahara S, et al. Targeting of tumor endothelial cells combining 2 Gy/day of X-ray with everolimus is the effective modality for overcoming clinically relevant radioresistant tumors. Cancer Med. 2014;3(2):310–321.
  • Bahrami A, Hasanzadeh M, Hassanian SM, et al. The Potential Value of the PI3K/Akt/mTOR signaling pathway for assessing prognosis in cervical cancer and as a target for therapy. J Cell Biochem. 2017;118(12):4163–4169.
  • Zhang L, Zhao Y, Tu Q, et al. The Roles of Programmed Cell Death Ligand-1/ Programmed Cell Death-1 (PD-L1/PD-1) in HPV-induced cervical cancer and potential for their use in blockade therapy. Curr Med Chem. 2021;28(5):893–909.
  • D’Alessandris N, Palaia I, Pernazza A, et al. PD-L1 expression is associated with tumor infiltrating lymphocytes that predict response to NACT in squamous cell cervical cancer. Virchows Arch. 2021;478(3):517–525.
  • Yoshino H, Sato Y, Nakano M. KPNB1 Inhibitor Importazole Reduces Ionizing Radiation-Increased Cell Surface PD-L1 expression by modulating expression and nuclear import of IRF1. Curr Issues Mol Biol. 2021;43(1):153–162.
  • Wu W, Chen J, Deng H, et al. Neoadjuvant everolimus plus letrozole versus fluorouracil, epirubicin and cyclophosphamide for ER-positive, HER2-negative breast cancer: a randomized pilot trial. BMC Cancer. 2021;21(1):862.
  • Takamori S, Takada K, Shimokawa M, et al. Predictive and prognostic impact of primary tumor-bearing lobe in nonsmall cell lung cancer patients treated with anti-PD −1 therapy. Int J Cancer. 2020;147(8):2327–2334.
  • Tu X, Qin B, Zhang Y, et al. PD-L1 (B7-H1) Competes with the RNA Exosome to Regulate the DNA damage response and can be targeted to sensitize to radiation or chemotherapy. Mol Cell. 2019;74(6):1215–1226 e1214.
  • Wang Y, Li G. PD-1/PD-L1 blockade in cervical cancer: current studies and perspectives. Front Med. 2019;13(4):438–450.
  • Yang C, Zhang J, Ding M, et al. Ki67 targeted strategies for cancer therapy. Clin Transl Oncol. 2018;20(5):570–575.
  • Chen K, Shang Z, Dai AL, et al. Novel PI3K/Akt/mTOR pathway inhibitors plus radiotherapy: strategy for non-small cell lung cancer with mutant RAS gene. Life Sci. 2020;255:117816.
  • Feng YQ, Gu SX, Chen YS, et al. Virtual Screening and Optimization of Novel mTOR inhibitors for radiosensitization of hepatocellular carcinoma. Drug Des Devel Ther. 2020;14:1779–1798.
  • Atkins MB, Clark JI, Quinn DI. Immune checkpoint inhibitors in advanced renal cell carcinoma: experience to date and future directions. Ann Oncol. 2017;28(7):1484–1494.
  • Choueiri TK, Fishman MN, Escudier B, et al. Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma. Clin Cancer Res. 2016;22(22):5461–5471.
  • Farolfi A, Schepisi G, Conteduca V, et al. Pharmacokinetics, pharmacodynamics and clinical efficacy of nivolumab in the treatment of metastatic renal cell carcinoma. Expert Opin Drug Metab Toxicol. 2016;12:1089–1096.
  • Grimm MO, Leucht K, Grunwald V, et al. New First Line treatment options of clear cell renal cell cancer patients with PD-1 or PD-L1 Immune-checkpoint inhibitor-based combination therapies. J Clin Med. 2020;9(2):565.
  • Solorzano-Ibarra F, Alejandre-Gonzalez AG, Ortiz-Lazareno PC, et al. Immune checkpoint expression on peripheral cytotoxic lymphocytes in cervical cancer patients: moving beyond the PD-1/PD-L1 axis. Clin Exp Immunol. 2021;204(1):78–95.
  • Boudousquie C, Bossi G, Hurst JM, et al. Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+and CD4+T cells. Immunology. 2017;152(3):425–438.
  • Farhood B, Najafi M, Mortezaee K. CD8+cytotoxic T lymphocytes in cancer immunotherapy: a review. J Cell Physiol. 2019;234(6):8509–8521.
  • Taguchi A, Furusawa A, Ito K, et al. Postradiotherapy persistent lymphopenia as a poor prognostic factor in patients with cervical cancer receiving radiotherapy: a single-center, retrospective study. Int J Clin Oncol. 2020;25(5):955–962.
  • Lugade AA, Moran JP, Gerber SA, et al. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J Immunol. 2005;174(12):7516–7523.
  • Bromwich EJ, McArdle PA, Canna K, et al. The relationship between T-lymphocyte infiltration, stage, tumour grade and survival in patients undergoing curative surgery for renal cell cancer. Br J Cancer. 2003;89(10):1906–1908.
  • Nakano O, Sato M, Naito Y, et al. Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res. 2001;61(13):5132–5136.
  • Fridman WH, Pages F, Sautes-Fridman C, et al. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306.
  • Harter PN, Bernatz S, Scholz A, et al. Distribution and prognostic relevance of tumor-infiltrating lymphocytes (TILs) and PD-1/PD-L1 immune checkpoints in human brain metastases. Oncotarget. 2015;6(38):40836–40849.
  • Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800.
  • Aqdas M, Maurya SK, Pahari S, et al. Immunotherapeutic Role of NOD-2 and TLR-4 signaling as an adjunct to antituberculosis chemotherapy. ACS Infect Dis. 2021;7(11):2999–3008.
  • Nicolet BP, Guislain A, van Alphen FPJ, et al. CD29 identifies IFN-γ–producing human CD8+T cells with an increased cytotoxic potential. Proc Natl Acad Sci U S A. 2020;117(12):6686–6696.
  • Chen HY, Xu L, Li LF, et al. Inhibiting the CD8(+) T cell infiltration in the tumor microenvironment after radiotherapy is an important mechanism of radioresistance. Sci Rep. 2018;8(1):11934.
  • Bolourian A, Mojtahedi Z. Monitoring of CD8(+) T-cell activity in mtor inhibitor-treated cancer patients for successful immunotherapy. Arch Med Res. 2016;47(5):401–402.
  • Ma Y, Li J, Wang H, et al. Combination of PD-1 Inhibitor and OX40 agonist induces tumor rejection and immune memory in mouse models of pancreatic cancer. Gastroenterology. 2020;159(1):306–319 e312.
  • Balanca CC, Salvioni A, Scarlata CM, et al. PD-1 blockade restores helper activity of tumor-infiltrating, exhausted PD-1hiCD39+ CD4 T cells. JCI Insight. 2021;6(2): DOI:10.1172/jci.insight.142513.
  • Cao G, Wang Q, Li G, et al. mTOR inhibition potentiates cytotoxicity of Vgamma4 gammadelta T cells via up-regulating NKG2D and TNF-alpha. J Leukoc Biol. 2016;100(5):1181–1189.
  • Saunders P, Cisterne A, Weiss J, et al. The mammalian target of rapamycin inhibitor RAD001 (everolimus) synergizes with chemotherapeutic agents, ionizing radiation and proteasome inhibitors in pre-B acute lymphocytic leukemia. Haematologica. 2011;96(1):69–77.