Изчерпаният клъстер на диференциацията (CD) 8+ Т-клетки губят имунологична активност поради митохондриална дисфункция, причинена от активиран от пероксизомен пролифератор рецептор γ коактиватор 1α (PGC-1α) инактивиране, което води до лоша прогноза при пациенти с рак. Тъй като наскоро беше съобщено, че водородният газ активира PGC ‑ 1α, настоящото проучване изследва дали възстановява изтощени CD8 + Т клетки, за да подобри прогнозата при пациенти с колоректален рак на стадий IV. Общо 55 пациенти с хистологично и клинично диагностициран стадий на IV колоректален карцином са били записани между юли 2014 г. и юли 2017 г. Пациентите са вдишвали газообразен водород в продължение на 3 часа на ден в собствените си домове и са получавали химиотерапия в Регионалния медицински център в Тамана (Тамана, Кумамото, Япония). CD8 + Т клетките бяха изолирани от периферната кръв и техният фенотип беше анализиран чрез поточна цитометрия.
Установено е, че изчерпаната терминална програмирана клетъчна смърт 1 (PD ‑ 1) + CD8 + Т клетки в периферната кръв са независимо свързани с по-лоша преживяемост без прогресия (PFS) и обща преживяемост (OS). По-специално, водородният газ намалява изобилието от изчерпани терминални PD-1 + CD8 + T клетки, увеличава този на активните терминални PD-1-CD8 + T клетки и подобрява PFS и OS времената, което предполага, че балансът между терминални PD1 + и PD1-CD8 + T клетките е от решаващо значение за прогнозата на рака. Следователно, в настоящото проучване е разработена нова система за класификация на пациентите (категория 1-4), базирана на тези два индекса, за да помогне за прогнозиране на прогнозата и терапевтичния отговор
Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ and Ahmed R: Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 439:682–687. 2006.2
Wherry EJ: T cell exhaustion. Nat Immunol. 12:492–499. 2011.3
Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE and Rosenberg SA: Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 114:1537–1544. 2009.4
Sun S, Fei X, Mao Y, Wang X, Garfield DH, Huang O, Wang J, Yuan F, Sun L, Yu Q, et al: PD-1+ immune cell infiltration inversely correlates with survival of operable breast cancer patients. Cancer Immunol Immunother. 63:395–406. 2014.5
Zarour HM: Reversing T-Cell dysfunction and exhaustion in cancer. Clin Cancer Res. 22:1856–1864. 2016.6
Lu X, Yang L, Yao D, Wu X, Li J, Liu X, Deng L, Huang C, Wang Y, Li D, et al: Tumor antigen-specific CD8+ T cells are negatively regulated by PD-1 and Tim-3 in human gastric cancer. Cell Immunol. 313:43–51. 2017.7
Scharping NE, Menk AV, Moreci RS, Whetstone RD, Dadey RE, Watkins SC, Ferris RL and Delgoffe GM: The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity. 45:374–388. 2016.8
Gros A, Parkhurst MR, Tran E, Pasetto A, Robbins PF, Ilyas S, Prickett TD, Gartner JJ, Crystal JS, Roberts IM, et al: Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat Med. 22:433–438. 2016.9
Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura KI, Katayama Y, Asoh S and Ohta S: Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 13:688–694. 2007.10
Zhou L, Wang X, Xue W, Xie K, Huang Y, Chen H, Gong G and Zeng Y: Beneficial effects of hydrogen-rich saline against spinal cord ischemia-reperfusion injury in rabbits. Brain Res. 1517:150–160. 2013.11
Hayashida K, Sano M, Ohsawa I, Shinmura K, Tamaki K, Kimura K, Endo J, Katayama T, Kawamura A, Kohsaka S, et al: Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury. Biochem Biophys Res Commun. 373:30–35. 2008.12
Zheng X, Zheng X, Mao Y, Cai J, Li Y, Liu W, Sun P, Zhang JH, Sun X and Yuan H: Hydrogen-rich saline protects against intestinal ischemia/reperfusion injury in rats. Free Radic Res. 43:478–484. 2009.13
Lee JW, Kim JI, Lee YA, Lee DH, Song CS, Cho YJ and Han JS: Inhaled hydrogen gas therapy for prevention of testicular ischemia/reperfusion injury in rats. J Pediatr Surg. 4:736–742. 2012.
14
Wang F, Yu G, Liu SY, Li JB, Wang JF, Bo LL, Qian LR, Sun XJ and Deng XM: Hydrogen-rich saline protects against renal ischemia/reperfusion injury in rats. J Surg Res. 167:e339–e344. 2011.15
Ji X, Tian Y, Xie K, Liu W, Qu Y and Fei Z: Protective effects of hydrogen-rich saline in a rat model of traumatic brain injury via reducing oxidative stress. J Surg Res. 178:e9–e16. 2012.16
Chen T, Tao Y, Yan W, Yang G, Chen X, Cao R, Zhang L, Xue J and Zhang Z: Protective effects of hydrogen-rich saline against N-methyl-N-nitrosourea-induced photoreceptor degeneration. Exp Eye Res. 148:65–73. 2016.17
Ren JD, Ma J, Hou J, Xiao WJ, Jin WH, Wu J and Fan KH: Hydrogen-rich saline inhibits NLRP3 inflammasome activation and attenuates experimental acute pancreatitis in mice. Mediators Inflamma. 2014:9308942014.
18
Nakao A, Toyoda Y, Sharma P, Evans M and Guthrie N: Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome-an open label pilot study. J Clin Biochem Nutr. 46:140–149. 2010.19
Amitani H, Asakawa A, Cheng K, Amitani M, Kaimoto K, Nakano M, Ushikai M, Li Y, Tsai M, Li JB, et al: Hydrogen improves glycemic control in type1 diabetic animal model by promoting glucose uptake into skeletal muscle. PLoS One. 8:e539132013.20
Li GM, Ji MH, Sun XJ, Zeng QT, Tian M, Fan YX, Li WY, Li N and Yang JJ: Effects of hydrogen-rich saline treatment on polymicrobial sepsis. J Surg Res. 181:279–286. 2013.21
Guo SX, Jin YY, Fang Q, You CG, Wang XG, Hu XL and Han CM: Beneficial effects of hydrogen-rich saline on early burn-wound progression in rats. PLoS One. 10:e01248972015.22
Kikkawa YS, Nakagawa T, Taniguchi M and Ito J: Hydrogen protects auditory hair cells from cisplatin-induced free radicals. Neurosci Lett. 579:125–129. 2014.23
Watanabe S, Fujita M, Ishihara M, Tachibana S, Yamamoto Y, Kaji T, Kawauchi T and Kanatani Y: Protective effect of inhalation of hydrogen gas on radiation-induced dermatitis and skin injury in rats. J Radiat Res. 55:1107–1113. 2014.24
Ushida T, Kotani T, Tsuda H, Imai K, Nakano T, Hirako S, Ito Y, Li H, Mano Y, Wang J, et al: Molecular hydrogen ameliorates several characteristics of preeclampsia in the Reduced Uterine Perfusion Pressure (RUPP) rat model. Free Radic Biol Med. 101:524–533. 2016.25
Ge L, Yang M, Yang NN, Yin XX and Song WG: Molecular hydrogen: A preventive and therapeutic medical gas for various diseases. Oncotarget. 8:102653–102673. 2017.26
Runtuwene J, Amitani H, Amitani M, Asakawa A, Cheng KC and Inui A: Hydrogen-water enhances 5-fluorouracil-induced inhibition of colon cancer. PeerJ. 3:e8592015.27
Wang D, Wang L, Zhang Y, Zhao Y and Chen G: Hydrogen gas inhibits lung cancer progression through targeting SMC3. Biomed Pharmacother. 104:788–797. 2018.28
Kamimura N, Ichimiya H, Iuchi K and Ohta S: Molecular hydrogen stimulates the gene expression of transcriptional coactivator PGC-1α to enhance fatty acid metabolism. NPJ Aging Mech Dis. 2:160082016.29
Handschin C and Spiegelman BM: Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev. 27:728–735. 2006.30
Sobin LH and Wittekind CH: UICC TNM Classification of malignant tumors. John Wiley and Sons; New York: 1997,
31
Tamura T, Hayashida K, Sano M, Suzuki M, Shibusawa T, Yoshizawa J, Kobayashi Y, Suzuki T, Ohta S, Morisaki H, et al: Feasibility and safety of hydrogen gas inhalation for post-cardiac arrest syndrome-First-in-Human Pilot Study. Circ J. 80:1870–1873. 2016.32
Cancer therapy evaluation program, common terminology criteria for adverse events, Version 3.0, DCTD, NCI, NIH, DHHS. Int J Clin Oncol 9. (Sup PIII). S1–S82. 2004.
33
Crespo J, Sun H, Welling TH, Tian Z and Zou W: T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol. 25:214–221. 2013.Related Articles