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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Single-Cell Transcriptome Analysis Reveals the M2 Macrophages and Exhausted T Cells and Intratumoral Heterogeneity in Triple-Negative Breast Cancer

Author(s): Lingyun Xu and Chen Li*

Volume 22, Issue 2, 2022

Published on: 18 June, 2021

Page: [294 - 312] Pages: 19

DOI: 10.2174/1871520621666210618100857

Price: $65

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Abstract

Background: Triple-Negative Breast Cancer (TNBC) is a highly heterogeneous and invasive malignancy that is characterized by high recurrence and mortality rates as well as extremely poor prognosis.

Objective: The objective of this study is to analyze T cells and Macrophages in the tumor microenvironment with the aim of identifying targets with therapeutic potential.

Methods: Single-cell sequencing data of TNBC patients from the GSE118389 dataset were analyzed to examine the immune environment and intratumoral heterogeneity of TNBC patients.

Results: Polarized alternatively activated macrophages (M2) and exhausted CD8+ T cells were identified in TNBC patients. Immunosuppressive checkpoint analysis revealed that levels of lymphocyte-activation gene 3 (LAG3) and T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) of exhausted T cells were significantly higher than levels of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyteassociated protein 4 (CTLA-4). This indicates that these markers are potential immunotherapy targets. Furthermore, analysis of significantly altered immune cell markers showed that several markers were associated with the prognosis of TNBC.

Conclusion: Overall, these findings demonstrate inter-tissue heterogeneity of TNBC, and provides novel therapeutic targets for the treatment of TNBC.

Keywords: Single-cell transcriptome, immune ecosystem, triple-negative breast cancer, activated macrophages, exhausted CD8+ T cells, immunosuppressive checkpoint.

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[1]
Hwang, S.Y.; Park, S.; Kwon, Y. Recent therapeutic trends and promising targets in triple negative breast cancer. Pharmacol. Ther., 2019, 199(9), 30-57.
[http://dx.doi.org/10.1016/j.pharmthera.2019.02.006] [PMID: 30825473]
[2]
Ren, X.; Ren, P.; Luo, S.; Ji, Q.; Xu, M.; Lu, N.; Wang, Y. Detection and analysis of phenotypes of tumor-associated macrophages in mouse model of spontaneous breast cancer. Xibao Yu Fenzi Mianyixue Zazhi, 2017, 33(6), 721-725.
[http://dx.doi.org/10.13423/j.cnki.cjcmi.008153] [PMID: 28615091]
[3]
Lijing, Z.; Zhixue, W.; Tingting, L.; Xing, Z.; Yixi, B. Roles of astragalus polysaccharides in coculture system of breast cancer cells and macrophages in Vitro. Chinese J. Immunol. J., 2017, 33(6), 469-476.
[http://dx.doi.org/10.13431/j.cnki.immunol.j.20170084]
[4]
Ohashi, R.; Yanagihara, K.; Namimatsu, S.; Sakatani, T.; Takei, H.; Naito, Z.; Shimizu, A. Osteoclast-like giant cells in invasive breast cancer predominantly possess M2-macrophage phenotype. Pathol. Res. Pract., 2018, 214(2), 253-258.
[http://dx.doi.org/10.1016/j.prp.2017.11.002] [PMID: 29129494]
[5]
Piao, Y.J.; Kim, H.S.; Hwang, E.H.; Woo, J.; Zhang, M.; Moon, W.K. Breast cancer cell-derived exosomes and macrophage polarization are associated with lymph node metastasis. Oncotarget, 2017, 9(7), 7398-7410.
[http://dx.doi.org/10.18632/oncotarget.23238] [PMID: 29484119]
[6]
Mills, C.D. Anatomy of a discovery: M1 and M2 macrophages. Front. Immunol., 2015, 6(5), 212.
[http://dx.doi.org/10.3389/fimmu.2015.00212] [PMID: 25999950]
[7]
Rhee, I. Diverse macrophages polarization in tumor microenvironment. Arch. Pharm. Res., 2016, 39(11), 1588-1596.
[http://dx.doi.org/10.1007/s12272-016-0820-y] [PMID: 27562774]
[8]
Gujam, F.J.A.; Edwards, J.; Mohammed, Z.M.A.; Going, J.J.; McMillan, D.C. The relationship between the tumour stroma percentage, clinicopathological characteristics and outcome in patients with operable ductal breast cancer. Br. J. Cancer, 2014, 111(1), 157-165.
[http://dx.doi.org/10.1038/bjc.2014.279] [PMID: 24874480]
[9]
Mao, Y.; Qu, Q.; Chen, X.; Huang, O.; Wu, J.; Shen, K. The prognostic value of tumor-infiltrating lymphocytes in breast cancer: A systematic review and meta-analysis. PLoS One, 2016, 11(4)e0152500
[http://dx.doi.org/10.1371/journal.pone.0152500] [PMID: 27073890]
[10]
Miyashita, M.; Sasano, H.; Tamaki, K.; Hirakawa, H.; Takahashi, Y.; Nakagawa, S.; Watanabe, G.; Tada, H.; Suzuki, A.; Ohuchi, N.; Ishida, T. Prognostic significance of tumor-infiltrating CD8+ and FOXP3+ lymphocytes in residual tumors and alterations in these parameters after neoadjuvant chemotherapy in triple-negative breast cancer: A retrospective multicenter study. Breast Cancer Res., 2015, 17(1), 124.
[http://dx.doi.org/10.1186/s13058-015-0632-x] [PMID: 26341640]
[11]
Asano, Y.; Kashiwagi, S.; Goto, W.; Kurata, K.; Noda, S.; Takashima, T.; Onoda, N.; Tanaka, S.; Ohsawa, M.; Hirakawa, K. Tumour-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to neoadjuvant chemotherapy of aggressive breast cancer. Br. J. Surg., 2016, 103(7), 845-854.
[http://dx.doi.org/10.1002/bjs.10127] [PMID: 26953091]
[12]
Mella, M.; Kauppila, J.H.; Karihtala, P.; Lehenkari, P.; Jukkola-Vuorinen, A.; Soini, Y.; Auvinen, P.; Vaarala, M.H.; Ronkainen, H.; Kauppila, S.; Haapasaari, K.M.; Vuopala, K.S.; Selander, K.S. Tumor infiltrating CD8+ T lymphocyte count is independent of tumor TLR9 status in treatment naïve triple negative breast cancer and renal cell carcinoma. OncoImmunology, 2015, 4(6)e1002726
[http://dx.doi.org/10.1080/2162402X.2014.1002726]
[13]
Chen, Z.; Chen, X.; Zhou, E.; Chen, G.; Qian, K.; Wu, X.; Miao, X.; Tang, Z.; Stephanie, F. Intratumoral CD8+ cytotoxic lymphocyte is a favorable prognostic marker in node-negative breast cancer. PLoS One, 2014, 9(4)e95475
[http://dx.doi.org/10.1371/journal.pone.0095475] [PMID: 24743335]
[14]
Liu, S.; Lachapelle, J.; Leung, S.; Gao, D.; Foulkes, W.D.; Nielsen, T.O. CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Res., 2012, 14(2), R48.
[http://dx.doi.org/10.1186/bcr3148] [PMID: 22420471]
[15]
Ali, H.R.; Provenzano, E.; Dawson, S.J.; Blows, F.M.; Liu, B.; Shah, M.; Earl, H.M.; Poole, C.J.; Hiller, L.; Dunn, J.A.; Bowden, S.J.; Twelves, C.; Bartlett, J.M.S.; Mahmoud, S.M.A.; Rakha, E.; Ellis, I.O.; Liu, S.; Gao, D.; Nielsen, T.O.; Pharoah, P.D.P.; Caldas, C. Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann. Oncol., 2014, 25(8), 1536-1543.
[http://dx.doi.org/10.1093/annonc/mdu191] [PMID: 24915873]
[16]
Le Mercier, I.; Lines, J.L.; Noelle, R.J. Beyond CTLA-4 and PD-1, the Generation Z of negative checkpoint regulators. Front. Immunol., 2015, 6(8), 418.
[http://dx.doi.org/10.3389/fimmu.2015.00418] [PMID: 26347741]
[17]
Hastings, W.D.; Anderson, D.E.; Kassam, N.; Koguchi, K.; Greenfield, E.A.; Kent, S.C.; Zheng, X.X.; Strom, T.B.; Hafler, D.A.; Kuchroo, V.K. TIM-3 is expressed on activated human CD4+ T cells and regulates Th1 and Th17 cytokines. Eur. J. Immunol., 2009, 39(9), 2492-2501.
[http://dx.doi.org/10.1002/eji.200939274] [PMID: 19676072]
[18]
Nakayama, M.; Akiba, H.; Takeda, K.; Kojima, Y.; Hashiguchi, M.; Azuma, M.; Yagita, H.; Okumura, K. Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood, 2009, 113(16), 3821-3830.
[http://dx.doi.org/10.1182/blood-2008-10-185884] [PMID: 19224762]
[19]
Kashio, Y.; Nakamura, K.; Abedin, M.J.; Seki, M.; Nishi, N.; Yoshida, N.; Nakamura, T.; Hirashima, M. Galectin-9 induces apoptosis through the calcium-calpain-caspase-1 pathway. J. Immunol., 2003, 170(7), 3631-3636.
[http://dx.doi.org/10.4049/jimmunol.170.7.3631] [PMID: 12646627]
[20]
Butler, A.; Hoffman, P.; Smibert, P.; Papalexi, E.; Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol., 2018, 36(5), 411-420.
[http://dx.doi.org/10.1038/nbt.4096] [PMID: 29608179]
[21]
Becht, E.; McInnes, L.; Healy, J.; Dutertre, C.A.; Kwok, I.W.H.; Ng, L.G.; Ginhoux, F.; Newell, E.W. Dimensionality reduction for visualizing single-cell data using UMAP. Nat. Biotechnol., 2018, 6(12), 11-12.
[http://dx.doi.org/10.1038/nbt.4314] [PMID: 30531897]
[22]
Zhang, X.; Lan, Y.; Xu, J.; Quan, F.; Zhao, E.; Deng, C.; Luo, T.; Xu, L.; Liao, G.; Yan, M.; Ping, Y.; Li, F.; Shi, A.; Bai, J.; Zhao, T.; Li, X.; Xiao, Y. CellMarker: A manually curated resource of cell markers in human and mouse. Nucleic Acids Res., 2019, 47(D1), D721-D728.
[http://dx.doi.org/10.1093/nar/gky900] [PMID: 30289549]
[23]
Hu, J.; Chen, Z.; Bao, L.; Zhou, L.; Hou, Y.; Liu, L.; Xiong, M.; Zhang, Y.; Wang, B.; Tao, Z.; Chen, K. Single-cell transcriptome analysis reveals intratumoral heterogeneity in ccRCC, which results in different clinical outcomes. Mol. Ther., 2020, 28(7), 1658-1672.
[http://dx.doi.org/10.1016/j.ymthe.2020.04.023] [PMID: 32396851]
[24]
Wang, Y.; Wang, R.; Zhang, S.; Song, S.; Jiang, C.; Han, G.; Wang, M.; Ajani, J.; Futreal, A.; Wang, L. ITALK: An R package to characterize and illustrate intercellular communication. bioRxiv, 2019.
[http://dx.doi.org/10.1101/507871]]
[25]
Qiu, X.; Mao, Q.; Tang, Y.; Wang, L.; Chawla, R.; Pliner, H.A.; Trapnell, C. Reversed graph embedding resolves complex single-cell trajectories. Nat. Methods, 2017, 14(10), 979-982.
[http://dx.doi.org/10.1038/nmeth.4402] [PMID: 28825705]
[26]
Ghayad, S.E.; Cohen, P.A. Inhibitors of the PI3K/Akt/mTOR pathway: New hope for breast cancer patients. Recent Patents Anticancer Drug Discov., 2010, 5(1), 29-57.
[http://dx.doi.org/10.2174/157489210789702208] [PMID: 19751211]
[27]
Lee, S.J.; Jang, B.C.; Lee, S.W.; Yang, Y.I.; Suh, S.I.; Park, Y.M.; Oh, S.; Shin, J.G.; Yao, S.; Chen, L.; Choi, I.H. Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-γ-induced upregulation of B7-H1 (CD274). FEBS Lett., 2006, 580(3), 755-762.
[http://dx.doi.org/10.1016/j.febslet.2005.12.093] [PMID: 16413538]
[28]
Gleimer, M.; Parham, P. Stress management: MHC class I and class I-like molecules as reporters of cellular stress. Immunity, 2003, 19(4), 469-477.
[http://dx.doi.org/10.1016/S1074-7613(03)00272-3] [PMID: 14563312]
[29]
Bedel, R.; Thiery-Vuillemin, A.; Grandclement, C.; Balland, J.; Remy-Martin, J.P.; Kantelip, B.; Pallandre, J.R.; Pivot, X.; Ferrand, C.; Tiberghien, P.; Borg, C. Novel role for STAT3 in transcriptional regulation of NK immune cell targeting receptor MICA on cancer cells. Cancer Res., 2011, 71(5), 1615-1626.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-4540] [PMID: 21257710]
[30]
Brown, J.A.; Dorfman, D.M.; Ma, F-R.; Sullivan, E.L.; Munoz, O.; Wood, C.R.; Greenfield, E.A.; Freeman, G.J. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J. Immunol., 2003, 170(3), 1257-1266.
[http://dx.doi.org/10.4049/jimmunol.170.3.1257] [PMID: 12538684]
[31]
Yan, W.; Liu, X.; Ma, H.; Zhang, H.; Song, X.; Gao, L.; Liang, X.; Ma, C. Tim-3 fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages. Gut, 2015, 64(10), 1593-1604.
[http://dx.doi.org/10.1136/gutjnl-2014-307671] [PMID: 25608525]
[32]
Schroder, K.; Hertzog, P.J.; Ravasi, T.; Hume, D.A. Interferon-γ: An overview of signals, mechanisms and functions. J. Leukoc. Biol., 2004, 75(2), 163-189.
[http://dx.doi.org/10.1189/jlb.0603252] [PMID: 14525967]
[33]
Schoop, R.; Wahl, P.; Le Hir, M.; Heemann, U.; Wang, M.; Wüthrich, R.P. Suppressed T-cell activation by IFN-γ-induced expression of PD-L1 on renal tubular epithelial cells. Nephrol. Dial. Transplant., 2004, 19(11), 2713-2720.
[http://dx.doi.org/10.1093/ndt/gfh423] [PMID: 15353579]
[34]
Nakazawa, A.; Dotan, I.; Brimnes, J.; Allez, M.; Shao, L.; Tsushima, F.; Azuma, M.; Mayer, L. The expression and function of costimulatory molecules B7H and B7-H1 on colonic epithelial cells. Gastroenterology, 2004, 126(5), 1347-1357.
[http://dx.doi.org/10.1053/j.gastro.2004.02.004] [PMID: 15131796]
[35]
Wintterle, S.; Schreiner, B.; Mitsdoerffer, M.; Schneider, D.; Chen, L.; Meyermann, R.; Weller, M.; Wiendl, H. Expression of the B7-related molecule B7-H1 by glioma cells: A potential mechanism of immune paralysis. Cancer Res., 2003, 63(21), 7462-7467.
[PMID: 14612546]
[36]
Mazanet, M.M.; Hughes, C.C.W. B7-H1 is expressed by human endothelial cells and suppresses T cell cytokine synthesis. J. Immunol., 2002, 169(7), 3581-3588.
[http://dx.doi.org/10.4049/jimmunol.169.7.3581] [PMID: 12244148]
[37]
Chávez-Galán, L.; Olleros, M.L.; Vesin, D.; Garcia, I. Much more than M1 and M2 macrophages, there are also CD169(+) and TCR(+) macrophages. Front. Immunol., 2015, 6(6), 263.
[http://dx.doi.org/10.3389/fimmu.2015.00263] [PMID: 26074923]
[38]
López-Knowles, E.; O’Toole, S.A.; McNeil, C.M.; Millar, E.K.A.; Qiu, M.R.; Crea, P.; Daly, R.J.; Musgrove, E.A.; Sutherland, R.L. PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specific mortality. Int. J. Cancer, 2010, 126(5), 1121-1131.
[http://dx.doi.org/10.1002/ijc.24831] [PMID: 19685490]
[39]
Cuenca-López, M.D.; Serrano-Heras, G.; Montero, J.C.; Corrales-Sánchez, V.; Gomez-Juarez, M.; Gascón-Escribano, M.J.; Morales, J.C.; Voisin, V.; Núñez, L.E.; Morís, F.; Bader, G.D.; Pandiella, A.; Ocaña, A. Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer. Oncotarget, 2015, 6(29), 27923-27937.
[http://dx.doi.org/10.18632/oncotarget.4736] [PMID: 26314846]
[40]
Wölfle, S.J.; Strebovsky, J.; Bartz, H.; Sähr, A.; Arnold, C.; Kaiser, C.; Dalpke, A.H.; Heeg, K. PD-L1 expression on tolerogenic APCs is controlled by STAT-3. Eur. J. Immunol., 2011, 41(2), 413-424.
[http://dx.doi.org/10.1002/eji.201040979] [PMID: 21268011]
[41]
Marotta, L.L.C.; Almendro, V.; Marusyk, A.; Shipitsin, M.; Schemme, J.; Walker, S.R.; Bloushtain-Qimron, N.; Kim, J.J.; Choudhury, S.A.; Maruyama, R.; Wu, Z.; Gönen, M.; Mulvey, L.A.; Bessarabova, M.O.; Huh, S.J.; Silver, S.J.; Kim, S.Y.; Park, S.Y.; Lee, H.E.; Anderson, K.S.; Richardson, A.L.; Nikolskaya, T.; Nikolsky, Y.; Liu, X.S.; Root, D.E.; Hahn, W.C.; Frank, D.A.; Polyak, K. The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24− stem cell-like breast cancer cells in human tumors. J. Clin. Invest., 2011, 121(7), 2723-2735.
[http://dx.doi.org/10.1172/JCI44745] [PMID: 21633165]
[42]
Zhang, W.; Yu, W.; Cai, G.; Zhu, J.; Zhang, C.; Li, S.; Guo, J.; Yin, G.; Chen, C.; Kong, L. A new synthetic derivative of cryptotanshinone KYZ3 as STAT3 inhibitor for triple-negative breast cancer therapy. Cell Death Dis., 2018, 9(11), 1098.
[http://dx.doi.org/10.1038/s41419-018-1139-z] [PMID: 30368518]
[43]
Guo, L.; Cao, C.; Goswami, S.; Huang, X.; Ma, L.; Guo, Y.; Yang, B.; Li, T.; Chi, Y.; Zhang, X.; Wu, J. Tumoral PD-1hiCD8+ T cells are partially exhausted and predict favorable outcome in triple-negative breast cancer. Clin. Sci. (Lond.), 2020, 134(7), 711-726.
[http://dx.doi.org/10.1042/CS20191261] [PMID: 32202617]
[44]
Platanias, L.C. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat. Rev. Immunol., 2005, 5(5), 375-386.
[http://dx.doi.org/10.1038/nri1604] [PMID: 15864272]
[45]
Garcia-Diaz, A.; Shin, D.S.; Moreno, B.H.; Saco, J.; Escuin-Ordinas, H.; Rodriguez, G.A.; Zaretsky, J.M.; Sun, L.; Hugo, W.; Wang, X.; Parisi, G.; Saus, C.P.; Torrejon, D.Y.; Graeber, T.G.; Comin-Anduix, B.; Hu-Lieskovan, S.; Damoiseaux, R.; Lo, R.S.; Ribas, A. interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep., 2019, 29(11), 3766.
[http://dx.doi.org/10.1016/j.celrep.2019.11.113] [PMID: 31825850]
[46]
Wang, Z.; Qin, J.; Zhao, J.; Li, J.; Li, D.; Popp, M.; Popp, F.; Alakus, H.; Kong, B.; Dong, Q.; Nelson, P.J. IFIT3 expression renders chemotherapy resistance through the regulation of mitochondria-associated apoptosis in pancreatic cancer. Eur. Surg. Res., 2019, 10(16), 7178-7192.
[http://dx.doi.org/10.7150/thno.43093]]
[47]
Pidugu, V.K.; Wu, M.M.; Yen, A.H.; Pidugu, H.B.; Chang, K.W.; Liu, C.J.; Lee, T.C. IFIT1 and IFIT3 promote oral squamous cell carcinoma metastasis and contribute to the anti-tumor effect of gefitinib via enhancing p-EGFR recycling. Oncogene, 2019, 38(17), 3232-3247.
[http://dx.doi.org/10.1038/s41388-018-0662-9] [PMID: 30626937]
[48]
Marchini, S.; Fruscio, R.; Clivio, L.; Beltrame, L.; Porcu, L.; Fuso Nerini, I.; Cavalieri, D.; Chiorino, G.; Cattoretti, G.; Mangioni, C.; Milani, R.; Torri, V.; Romualdi, C.; Zambelli, A.; Romano, M.; Signorelli, M.; di Giandomenico, S.; D’Incalci, M. Resistance to platinum-based chemotherapy is associated with epithelial to mesenchymal transition in epithelial ovarian cancer. Eur. J. Cancer, 2013, 49(2), 520-530.
[http://dx.doi.org/10.1016/j.ejca.2012.06.026] [PMID: 22897840]
[49]
Zhang, W.; Feng, M.; Zheng, G.; Chen, Y.; Wang, X.; Pen, B.; Yin, J.; Yu, Y.; He, Z. Chemoresistance to 5-fluorouracil induces epithelial-mesenchymal transition via up-regulation of Snail in MCF7 human breast cancer cells. Biochem. Biophys. Res. Commun., 2012, 417(2), 679-685.
[http://dx.doi.org/10.1016/j.bbrc.2011.11.142] [PMID: 22166209]
[50]
Tian, S.B.; Yu, J.C.; Liu, Y.Q.; Kang, W.M.; Ma, Z.Q.; Ye, X.; Yan, C. MiR-30b suppresses tumor migration and invasion by targeting EIF5A2 in gastric cancer. World J. Gastroenterol., 2015, 21(31), 9337-9347.
[http://dx.doi.org/10.3748/wjg.v21.i31.9337] [PMID: 26309359]
[51]
Fujimura, K.; Wright, T.; Strnadel, J.; Kaushal, S.; Metildi, C.; Lowy, A.M.; Bouvet, M.; Kelber, J.A.; Klemke, R.L.A. A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic cancer. Cancer Res., 2014, 74(22), 6671-6681.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-1031] [PMID: 25261239]
[52]
Liu, R.R.; Lv, Y.S.; Tang, Y.X.; Wang, Y.F.; Chen, X.L.; Zheng, X.X.; Xie, S.Z.; Cai, Y.; Yu, J.; Zhang, X.N. Eukaryotic translation initiation factor 5A2 regulates the migration and invasion of hepatocellular carcinoma cells via pathways involving reactive oxygen species. Oncotarget, 2016, 7(17), 24348-24360.
[http://dx.doi.org/10.18632/oncotarget.8324] [PMID: 27028999]
[53]
Calandra, T.; Roger, T. Macrophage migration inhibitory factor: A regulator of innate immunity. Nat. Rev. Immunol., 2003, 3(10), 791-800.
[http://dx.doi.org/10.1038/nri1200] [PMID: 14502271]
[54]
Yuan, Y.; Jiang, Y.C.; Sun, C.K.; Chen, Q.M. Role of the tumor microenvironment in tumor progression and the clinical applications. (Review) Oncol. Rep., 2016, 35(5), 2499-2515.
[http://dx.doi.org/10.3892/or.2016.4660] [PMID: 26986034]
[55]
Lippitz, B.E. Cytokine patterns in patients with cancer: A systematic review. Lancet Oncol., 2013, 14(6), e218-e228.
[http://dx.doi.org/10.1016/S1470-2045(12)70582-X] [PMID: 23639322]
[56]
Song, Z.; Liu, T.; Chen, J.; Ge, C.; Zhao, F.; Zhu, M.; Chen, T.; Cui, Y.; Tian, H.; Yao, M.; Li, J.; Li, H. HIF-1α-induced RIT1 promotes liver cancer growth and metastasis and its deficiency increases sensitivity to sorafenib. Cancer Lett., 2019, 460(3), 96-107.
[http://dx.doi.org/10.1016/j.canlet.2019.06.016] [PMID: 31247273]
[57]
Khalil, A.; Nemer, G. The potential oncogenic role of the RAS-like GTP-binding gene RIT1 in glioblastoma. Cancer Biomark., 2020, 29(4), 509-519.
[http://dx.doi.org/10.3233/CBM-191264] [PMID: 32831193]
[58]
Han, J-I.; Huang, N.N.; Kim, D.U.; Kehrl, J.H. RGS1 and RGS13 mRNA silencing in a human B lymphoma line enhances responsiveness to chemoattractants and impairs desensitization. J. Leukoc. Biol., 2006, 79(6), 1357-1368.
[http://dx.doi.org/10.1189/jlb.1105693] [PMID: 16565322]
[59]
Koga, H.; Imada, K.; Ueda, M.; Hishizawa, M.; Uchiyama, T. Identification of differentially expressed molecules in adult T-cell leukemia cells proliferating in vivo. Cancer Sci., 2004, 95(5), 411-417.
[http://dx.doi.org/10.1111/j.1349-7006.2004.tb03224.x] [PMID: 15132768]
[60]
Pak, H.K.; Gil, M.; Lee, Y.; Lee, H.; Lee, A.N.; Roh, J.; Park, C.S. Regulator of G protein signaling 1 suppresses CXCL12-mediated migration and AKT activation in RPMI 8226 human plasmacytoma cells and plasmablasts. PLoS One, 2015, 10(4)e0124793
[http://dx.doi.org/10.1371/journal.pone.0124793] [PMID: 25897806]
[61]
Kashani-Sabet, M.; Nosrati, M.; Miller, J.R., III; Sagebiel, R.W.; Leong, S.P.L.; Lesniak, A.; Tong, S.; Lee, S.J.; Kirkwood, J.M. Prospective validation of molecular prognostic markers in cutaneous melanoma: A correlative analysis of E1690. Clin. Cancer Res., 2017, 23(22), 6888-6892.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-1317] [PMID: 28790109]
[62]
Hellmann, M.D.; Rizvi, N.A.; Goldman, J.W.; Gettinger, S.N.; Borghaei, H.; Brahmer, J.R.; Ready, N.E.; Gerber, D.E.; Chow, L.Q.; Juergens, R.A.; Shepherd, F.A.; Laurie, S.A.; Geese, W.J.; Agrawal, S.; Young, T.C.; Li, X.; Antonia, S.J. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): Results of an open-label, phase 1, multicohort study. Lancet Oncol., 2017, 18(1), 31-41.
[http://dx.doi.org/10.1016/S1470-2045(16)30624-6] [PMID: 27932067]
[63]
Weber, J.; Mandala, M.; Del Vecchio, M.; Gogas, H.J.; Arance, A.M.; Cowey, C.L.; Dalle, S.; Schenker, M.; Chiarion-Sileni, V.; Marquez-Rodas, I.; Grob, J.J.; Butler, M.O.; Middleton, M.R.; Maio, M.; Atkinson, V.; Queirolo, P.; Gonzalez, R.; Kudchadkar, R.R.; Smylie, M.; Meyer, N.; Mortier, L.; Atkins, M.B.; Long, G.V.; Bhatia, S.; Lebbé, C.; Rutkowski, P.; Yokota, K.; Yamazaki, N.; Kim, T.M.; de Pril, V.; Sabater, J.; Qureshi, A.; Larkin, J.; Ascierto, P.A. CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N. Engl. J. Med., 2017, 377(19), 1824-1835.
[http://dx.doi.org/10.1056/NEJMoa1709030] [PMID: 28891423]
[64]
Du, X.; Tang, F.; Liu, M.; Su, J.; Zhang, Y.; Wu, W.; Devenport, M.; Lazarski, C.A.; Zhang, P.; Wang, X.; Ye, P.; Wang, C.; Hwang, E.; Zhu, T.; Xu, T.; Zheng, P.; Liu, Y. A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy. Cell Res., 2018, 28(4), 416-432.
[http://dx.doi.org/10.1038/s41422-018-0011-0] [PMID: 29472691]
[65]
Du, X.; Liu, M.; Su, J.; Zhang, P.; Tang, F.; Ye, P.; Devenport, M.; Wang, X.; Zhang, Y.; Liu, Y.; Zheng, P. Uncoupling therapeutic from immunotherapy-related adverse effects for safer and effective anti-CTLA-4 antibodies in CTLA4 humanized mice. Cell Res., 2018, 28(4), 433-447.
[http://dx.doi.org/10.1038/s41422-018-0012-z] [PMID: 29463898]
[66]
Li, C.; Chen, X.; Yu, X.; Zhu, Y.; Ma, C.; Xia, R.; Ma, J.; Gu, C.; Ye, L.; Wu, D. Tim-3 is highly expressed in T cells in acute myeloid leukemia and associated with clinicopathological prognostic stratification. Int. J. Clin. Exp. Pathol., 2014, 7(10), 6880-6888.
[PMID: 25400771]
[67]
Komohara, Y.; Morita, T.; Annan, D.A.; Horlad, H.; Ohnishi, K.; Yamada, S.; Nakayama, T.; Kitada, S.; Suzu, S.; Kinoshita, I.; Dosaka-Akita, H.; Akashi, K.; Takeya, M.; Jinushi, M. The coordinated actions of TIM-3 on cancer and myeloid cells in the regulation of tumorigenicity and clinical prognosis in clear cell renal cell carcinomas. Cancer Immunol. Res., 2015, 3(9), 999-1007.
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0156] [PMID: 25783986]
[68]
Han, S.; Feng, S.; Xu, L.; Shi, W.; Wang, X.; Wang, H.; Yu, C.; Dong, T.; Xu, M.; Liang, G. Tim-3 on peripheral CD4+ and CD8+ T cells is involved in the development of glioma. DNA Cell Biol., 2014, 33(4), 245-250.
[http://dx.doi.org/10.1089/dna.2013.2306] [PMID: 24512143]
[69]
Jiang, J.; Jin, M.S.; Kong, F.; Cao, D.; Ma, H.X.; Jia, Z.; Wang, Y.P.; Suo, J.; Cao, X. Decreased galectin-9 and increased Tim-3 expression are related to poor prognosis in gastric cancer. PLoS One, 2013, 8(12)e81799
[http://dx.doi.org/10.1371/journal.pone.0081799] [PMID: 24339967]
[70]
Anderson, A.C. Tim-3: An emerging target in the cancer immunotherapy landscape. Cancer Immunol. Res., 2014, 2(5), 393-398.
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0039] [PMID: 24795351]
[71]
Sakuishi, K.; Apetoh, L.; Sullivan, J.M.; Blazar, B.R.; Kuchroo, V.K.; Anderson, A.C. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med., 2010, 207(10), 2187-2194.
[http://dx.doi.org/10.1084/jem.20100643] [PMID: 20819927]
[72]
Jacquemin, G.; Margiotta, D.; Kasahara, A.; Bassoy, E.Y.; Walch, M.; Thiery, J.; Lieberman, J.; Martinvalet, D. Granzyme B-induced mitochondrial ROS are required for apoptosis. Cell Death Differ., 2015, 22(5), 862-874.
[http://dx.doi.org/10.1038/cdd.2014.180] [PMID: 25361078]
[73]
Kato, T.; Tomiyama, E.; Koh, Y.; Matsushita, M.; Hayashi, Y.; Nakano, K.; Ishizuya, Y.U.; Wang, C.; Hatano, K.; Kawashima, A.; Ujike, T.; Kawasaki, K.; Morii, E.; Gotoh, K.; Eguchi, H.; Kiyotani, K.; Fujita, K.; Nonomura, N.; Uemura, M. A potential mechanism of anticancer immune response coincident with immune-related adverse events in patients With renal cell carcinoma. Anticancer Res., 2020, 40(9), 4875-4883.
[http://dx.doi.org/10.21873/anticanres.14490] [PMID: 32878775]
[74]
Wang, F.; Long, J.; Li, L.; Zhao, Z.B.; Wei, F.; Yao, Y.; Qiu, W.J.; Wu, Z.X.; Luo, Q.Q.; Liu, W.; Quan, Y.B.; Lian, Z.X.; Cao, J. Mutations in the notch signalling pathway are associated with enhanced anti-tumour immunity in colorectal cancer. J. Cell. Mol. Med., 2020, 24(20), 12176-12187.
[http://dx.doi.org/10.1111/jcmm.15867] [PMID: 32924269]
[75]
Yang, L-S.; Shi, C-Y.; Liang, Y-H.; Liu, T.; Hou, X-R.; Tian, X-D.; Wang, X-Y. Bioinformatics analysis of programmed cell death ligand 1 co-expression genes and their regulatory network in head and neck squamous cell carcinoma. Hua Xi Kou Qiang Yi Xue Za Zhi, 2019, 37(5), 516-520.
[http://dx.doi.org/10.7518/hxkq.2019.05.012] [PMID: 31721500]
[76]
Wei, S.C.; Duffy, C.R.; Allison, J.P. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov., 2018, 8(9), 1069-1086.
[http://dx.doi.org/10.1158/2159-8290.CD-18-0367] [PMID: 30115704]
[77]
Ishida, Y.; Agata, Y.; Shibahara, K.; Honjo, T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J., 1992, 11(11), 3887-3895.
[http://dx.doi.org/10.1002/j.1460-2075.1992.tb05481.x] [PMID: 1396582]
[78]
Gradishar, W.J.; Anderson, B.O.; Balassanian, R.; Blair, S.L.; Burstein, H.J.; Cyr, A.; Elias, A.D.; Farrar, W.B.; Forero, A.; Giordano, S.H.; Goetz, M.; Goldstein, L.J.; Hudis, C.A.; Isakoff, S.J.; Marcom, P.K.; Mayer, I.A.; McCormick, B.; Moran, M.; Patel, S.A.; Pierce, L.J.; Reed, E.C.; Salerno, K.E.; Schwartzberg, L.S.; Smith, K.L.; Smith, M.L.; Soliman, H.; Somlo, G.; Telli, M.; Ward, J.H.; Shead, D.A.; Kumar, R. Breast cancer version 2.2015. J. Natl. Compr. Canc. Netw., 2015, 13(4), 448-475.
[http://dx.doi.org/10.6004/jnccn.2015.0060] [PMID: 25870381]
[79]
Rida, P.; Ogden, A.; Ellis, I.O.; Varga, Z.; Wolff, A.C.; Traina, T.A.; Hatzis, C.; Palmer, J.R.; Ambrosone, C.B.; Lehmann, B.D.; Nanda, R.; Montgomery Rice, V.; Brawley, O.W.; Torres, M.A.; Rakha, E.; Aneja, R. First international TNBC conference meeting report. Breast Cancer Res. Treat., 2018, 169(3), 407-412.
[http://dx.doi.org/10.1007/s10549-018-4692-3] [PMID: 29417299]
[80]
Larkin, J.; Chiarion-Sileni, V.; Gonzalez, R.; Grob, J.J.; Cowey, C.L.; Lao, C.D.; Schadendorf, D.; Dummer, R.; Smylie, M.; Rutkowski, P.; Ferrucci, P.F.; Hill, A.; Wagstaff, J.; Carlino, M.S.; Haanen, J.B.; Maio, M.; Marquez-Rodas, I.; McArthur, G.A.; Ascierto, P.A.; Long, G.V.; Callahan, M.K.; Postow, M.A.; Grossmann, K.; Sznol, M.; Dreno, B.; Bastholt, L.; Yang, A.; Rollin, L.M.; Horak, C.; Hodi, F.S.; Wolchok, J.D. Combined nivolumab and Ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med., 2015, 373(1), 23-34.
[http://dx.doi.org/10.1056/NEJMoa1504030] [PMID: 26027431]
[81]
Wolchok, J.D.; Chiarion-Sileni, V.; Gonzalez, R.; Rutkowski, P.; Grob, J.J.; Cowey, C.L.; Lao, C.D.; Wagstaff, J.; Schadendorf, D.; Ferrucci, P.F.; Smylie, M.; Dummer, R.; Hill, A.; Hogg, D.; Haanen, J.; Carlino, M.S.; Bechter, O.; Maio, M.; Marquez-Rodas, I.; Guidoboni, M.; McArthur, G.; Lebbé, C.; Ascierto, P.A.; Long, G.V.; Cebon, J.; Sosman, J.; Postow, M.A.; Callahan, M.K.; Walker, D.; Rollin, L.; Bhore, R.; Hodi, F.S.; Larkin, J. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med., 2017, 377(14), 1345-1356.
[http://dx.doi.org/10.1056/NEJMoa1709684] [PMID: 28889792]
[82]
Motzer, R.J.; Tannir, N.M.; McDermott, D.F.; Arén Frontera, O.; Melichar, B.; Choueiri, T.K.; Plimack, E.R.; Barthélémy, P.; Porta, C.; George, S.; Powles, T.; Donskov, F.; Neiman, V.; Kollmannsberger, C.K.; Salman, P.; Gurney, H.; Hawkins, R.; Ravaud, A.; Grimm, M.O.; Bracarda, S.; Barrios, C.H.; Tomita, Y.; Castellano, D.; Rini, B.I.; Chen, A.C.; Mekan, S.; McHenry, M.B.; Wind-Rotolo, M.; Doan, J.; Sharma, P.; Hammers, H.J.; Escudier, B. CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med., 2018, 378(14), 1277-1290.
[http://dx.doi.org/10.1056/NEJMoa1712126] [PMID: 29562145]
[83]
Hellmann, M.D.; Ciuleanu, T.E.; Pluzanski, A.; Lee, J.S.; Otterson, G.A.; Audigier-Valette, C.; Minenza, E.; Linardou, H.; Burgers, S.; Salman, P.; Borghaei, H.; Ramalingam, S.S.; Brahmer, J.; Reck, M.; O’Byrne, K.J.; Geese, W.J.; Green, G.; Chang, H.; Szustakowski, J.; Bhagavatheeswaran, P.; Healey, D.; Fu, Y.; Nathan, F.; Paz-Ares, L. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med., 2018, 378(22), 2093-2104.
[http://dx.doi.org/10.1056/NEJMoa1801946] [PMID: 29658845]
[84]
Waterhouse, P.; Penninger, J.M.; Timms, E.; Wakeham, A.; Shahinian, A.; Lee, K.P.; Thompson, C.B.; Griesser, H.; Mak, T.W.; Briggs, Z.; Hou, T.Z.; Futter, C.E.; Anderson, G.; Walker, L.S.K.; Sansom, D.M. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science, 1995, 270(5238), 985-988.
[http://dx.doi.org/10.1126/science.270.5238.985] [PMID: 7481803]
[85]
Tivol, E.A.; Borriello, F.; Schweitzer, A.N.; Lynch, W.P.; Bluestone, J.A.; Sharpe, A.H. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity, 1995, 3(5), 541-547.
[http://dx.doi.org/10.1016/1074-7613(95)90125-6] [PMID: 7584144]
[86]
Chambers, C.A.; Sullivan, T.J.; Allison, J.P. Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity, 1997, 7(6), 885-895.
[http://dx.doi.org/10.1016/S1074-7613(00)80406-9] [PMID: 9430233]
[87]
Zhou, S.L.; Zhou, Z.J.; Hu, Z.Q.; Huang, X.W.; Wang, Z.; Chen, E.B.; Fan, J.; Cao, Y.; Dai, Z.; Zhou, J. Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology, 2016, 150(7), 1646-1658.e17.
[http://dx.doi.org/10.1053/j.gastro.2016.02.040] [PMID: 26924089]
[88]
Komohara, Y.; Takeya, M. CAFs and TAMs: Maestros of the tumour microenvironment. J. Pathol., 2017, 241(3), 313-315.
[http://dx.doi.org/10.1002/path.4824] [PMID: 27753093]
[89]
Bolli, E.; Movahedi, K.; Laoui, D.; Van Ginderachter, J.A. Novel insights in the regulation and function of macrophages in the tumor microenvironment.Curr. Opin. Oncol., 2017, 29(1), 55-61.,
[http://dx.doi.org/10.1097/CCO.0000000000000344] [PMID: 27792052]

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