Complex interplay between tumor microenvironment and cancer therapy

Abstract

Tumor microenvironment (TME) is comprised of cellular and non-cellular components that exist within and around the tumor mass. The TME is highly dynamic and its importance in different stages of cancer progression has been well recognized. A growing body of evidence suggests that TME also plays pivotal roles in cancer treatment responses. TME is significantly remodeled upon cancer therapies, and such change either enhances the responses or induces drug resistance. Given the importance of TME in tumor progression and therapy resistance, strategies that remodel TME to improve therapeutic responses are under developing. In this review, we provide an overview of the essential components in TME and the remodeling of TME in response to anti-cancer treatments. We also summarize the strategies that aim to enhance therapeutic efficacy by modulating TME.

Keywords

tumor microenvironment / therapy response / treatment resistance

References

[1] Fukumura D, Jain RK. Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize. J Cell Biochem 2007; 101(4): 937–949

[2] Justus CR, Dong L, Yang LV. Acidic tumor microenvironment and pH-sensing G protein-coupled receptors. Front Physiol 2013; 4: 354

[3] Justus CR, Sanderlin EJ, Yang LV. Molecular connections between cancer cell metabolism and the tumor microenvironment. Int J Mol Sci 2015; 16(5): 11055–11086

[4] Lin CS, Lee HT, Lee MH, Pan SC, Ke CY, Chiu AW, Wei YH. Role of mitochondrial DNA copy number alteration in human renal cell carcinoma. Int J Mol Sci 2016; 17(6): E814

[5] Ruella M, Klichinsky M, Kenderian SS, Shestova O, Ziober A, Kraft DO, Feldman M, Wasik MA, June CH, Gill S. Overcoming the immunosuppressive tumor microenvironment of Hodgkin lymphoma using chimeric antigen receptor T cells. Cancer Discov 2017; 7(10): 1154–1167

[6] Liu Q, Liao Q, Zhao Y. Chemotherapy and tumor microenvironment of pancreatic cancer. Cancer Cell Int 2017; 17(1): 68

[7] Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer 2012; 12(12): 860–875

[8] Ito K, Hamamichi S, Abe T, Akagi T, Shirota H, Kawano S, Asano M, Asano O, Yokoi A, Matsui J, Umeda IO, Fujii H. Antitumor effects of eribulin depend on modulation of the tumor microenvironment by vascular remodeling in mouse models. Cancer Sci 2017; 108(11): 2273–2280

[9] Grantab R, Sivananthan S, Tannock IF. The penetration of anticancer drugs through tumor tissue as a function of cellular adhesion and packing density of tumor cells. Cancer Res 2006; 66(2): 1033–1039

[10] Netti PA, Berk DA, Swartz MA, Grodzinsky AJ, Jain RK. Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res 2000; 60(9): 2497–2503

[11] Wu T, Dai Y. Tumor microenvironment and therapeutic response. Cancer Lett 2017; 387: 61–68

[12] Chen Q, Liu G, Liu S, Su H, Wang Y, Li J, Luo C. Remodeling the tumor microenvironment with emerging nanotherapeutics. Trends Pharmacol Sci 2018; 39(1): 59–74

[13] Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene 2008; 27(45): 5904–5912

[14] Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer 2011; 105(1): 93–103

[15] Fridman WH, Pagès F, Sautès-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 2012; 12(4): 298–306

[16] Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N, Knoblaugh S, Cado D, Greenberg NM, Raulet DH. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 2008; 28(4): 571–580

[17] Coca S, Perez-Piqueras J, Martinez D, Colmenarejo A, Saez MA, Vallejo C, Martos JA, Moreno M. The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer 1997; 79(12): 2320–2328

[18] Villegas FR, Coca S, Villarrubia VG, Jiménez R, Chillón MJ, Jareño J, Zuil M, Callol L. Prognostic significance of tumor infiltrating natural killer cells subset CD57 in patients with squamous cell lung cancer. Lung Cancer 2002; 35(1): 23–28

[19] Taketomi A, Shimada M, Shirabe K, Kajiyama K, Gion T, Sugimachi K. Natural killer cell activity in patients with hepatocellular carcinoma: a new prognostic indicator after hepatectomy. Cancer 1998; 83(1): 58–63

[20] Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Che X, Iwashige H, Aridome K, Hokita S, Aikou T. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 2000; 88(3): 577–583

[21] Takeuchi H, Maehara Y, Tokunaga E, Koga T, Kakeji Y, Sugimachi K. Prognostic significance of natural killer cell activity in patients with gastric carcinoma: a multivariate analysis. Am J Gastroenterol 2001; 96(2): 574–578

[22] Larsen SK, Gao Y, Basse PH. NK cells in the tumor microenvironment. Crit Rev Oncog 2014; 19(1-2): 91–105

[23] Shang B, Liu Y, Jiang SJ, Liu Y. Prognostic value of tumor-infiltrating FoxP3⁺ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep 2015; 5(1): 15179

[24] Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25⁺CD4⁺ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 1999; 163(10): 5211–5218

[25] Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor α) monoclonal antibody. Cancer Res 1999; 59(13): 3128–3133

[26] Yamaguchi T, Sakaguchi S. Regulatory T cells in immune surveillance and treatment of cancer. Semin Cancer Biol 2006; 16(2): 115–123

[27] Campbell DJ, Koch MA. Treg cells: patrolling a dangerous neighborhood. Nat Med 2011; 17(8): 929–930

[28] Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013; 19(11): 1423–1437

[29] Chen Y, Zhang S, Wang Q, Zhang X. Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein. J Hematol Oncol 2017; 10(1): 36

[30] Yang L, Wang F, Wang L, Huang L, Wang J, Zhang B, Zhang Y. CD163⁺ tumor-associated macrophage is a prognostic biomarker and is associated with therapeutic effect on malignant pleural effusion of lung cancer patients. Oncotarget 2015; 6(12): 10592–10603

[31] Shigeoka M, Urakawa N, Nakamura T, Nishio M, Watajima T, Kuroda D, Komori T, Kakeji Y, Semba S, Yokozaki H. Tumor associated macrophage expressing CD204 is associated with tumor aggressiveness of esophageal squamous cell carcinoma. Cancer Sci 2013; 104(8): 1112–1119

[32] Kim KJ, Wen XY, Yang HK, Kim WH, Kang GH. Prognostic implication of M2 macrophages are determined by the proportional balance of tumor associated macrophages and tumor infiltrating lymphocytes in microsatellite-unstable gastric carcinoma. PLoS One 2015; 10(12): e0144192

[33] Grivennikov SI, Wang K, Mucida D, Stewart CA, Schnabl B, Jauch D, Taniguchi K, Yu GY, Osterreicher CH, Hung KE, Datz C, Feng Y, Fearon ER, Oukka M, Tessarollo L, Coppola V, Yarovinsky F, Cheroutre H, Eckmann L, Trinchieri G, Karin M. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 2012; 491(7423): 254–258

[34] Greten FR, Karin M. The IKK/NF-κB activation pathway—a target for prevention and treatment of cancer. Cancer Lett 2004; 206(2): 193–199

[35] Kong L, Zhou Y, Bu H, Lv T, Shi Y, Yang J. Deletion of interleukin-6 in monocytes/macrophages suppresses the initiation of hepatocellular carcinoma in mice. J Exp Clin Cancer Res 2016; 35(1): 131

[36] Ueha S, Shand FH, Matsushima K. Myeloid cell population dynamics in healthy and tumor-bearing mice. Int Immunopharmacol 2011; 11(7): 783–788

[37] Damuzzo V, Pinton L, Desantis G, Solito S, Marigo I, Bronte V, Mandruzzato S. Complexity and challenges in defining myeloid-derived suppressor cells. Cytometry B Clin Cytom 2015; 88(2): 77–91

[38] Hossain F, Al-Khami AA, Wyczechowska D, Hernandez C, Zheng L, Reiss K, Valle LD, Trillo-Tinoco J, Maj T, Zou W, Rodriguez PC, Ochoa AC. Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies. Cancer Immunol Res 2015; 3(11): 1236–1247

[39] Xing F, Saidou J, Watabe K. Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front Biosci (Landmark Ed) 2011; 15:166–179

[40] Grum-Schwensen B, Klingelhofer J, Berg CH, El-Naaman C, Grigorian M, Lukanidin E, Ambartsumian N. Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene. Cancer Res 2005; 65(9): 3772–3780

[41] Goh PP, Sze DM, Roufogalis BD. Molecular and cellular regulators of cancer angiogenesis. Curr Cancer Drug Targets 2007; 7(8): 743–758

[42] Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005; 121(3): 335–348

[43] Li G, Satyamoorthy K, Meier F, Berking C, Bogenrieder T, Herlyn M. Function and regulation of melanoma-stromal fibroblast interactions: when seeds meet soil. Oncogene 2003; 22(20): 3162–3171

[44] Cunha GR, Hayward SW, Wang YZ. Role of stroma in carcinogenesis of the prostate. Differentiation 2002; 70(9-10): 473–485

[45] Bindra RS, Glazer PM. Genetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesis. Mutat Res 2005; 569(1-2): 75–85

[46] Yuan J, Glazer PM. Mutagenesis induced by the tumor microenvironment. Mutat Res 1998; 400(1-2): 439–446

[47] Koukourakis MI, Giatromanolaki A, Harris AL, Sivridis E. Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Res 2006; 66(2): 632–637

[48] Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420(6917): 860–867

[49] Camps JL, Chang SM, Hsu TC, Freeman MR, Hong SJ, Zhau HE, von Eschenbach AC, Chung LW. Fibroblast-mediated acceleration of human epithelial tumor growth in vivo. Proc Natl Acad Sci USA 1990; 87(1): 75–79

[50] Imai K. Matrix metalloproteinases and cancer cell invasion and metastasis. Tanpakushitsu Kakusan Koso 1997; 42(10 Suppl): 1694–1700 (in Japanese)

[51] Akino T, Hida K, Hida Y, Tsuchiya K, Freedman D, Muraki C, Ohga N, Matsuda K, Akiyama K, Harabayashi T, Shinohara N, Nonomura K, Klagsbrun M, Shindoh M. Cytogenetic abnormalities of tumor-associated endothelial cells in human malignant tumors. Am J Pathol 2009; 175(6): 2657–2667

[52] Amin DN, Hida K, Bielenberg DR, Klagsbrun M. Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. Cancer Res 2006; 66(4): 2173–2180

[53] Tsuchiya K, Hida K, Hida Y, Muraki C, Ohga N, Akino T, Kondo T, Miseki T, Nakagawa K, Shindoh M, Harabayashi T, Shinohara N, Nonomura K, Kobayashi M. Adrenomedullin antagonist suppresses tumor formation in renal cell carcinoma through inhibitory effects on tumor endothelial cells and endothelial progenitor mobilization. Int J Oncol 2010; 36(6): 1379–1386

[54] Matsuda K, Ohga N, Hida Y, Muraki C, Tsuchiya K, Kurosu T, Akino T, Shih SC, Totsuka Y, Klagsbrun M, Shindoh M, Hida K. Isolated tumor endothelial cells maintain specific character during long-term culture. Biochem Biophys Res Commun 2010; 394(4): 947–954

[55] Maishi N, Ohba Y, Akiyama K, Ohga N, Hamada J, Nagao-Kitamoto H, Alam MT, Yamamoto K, Kawamoto T, Inoue N, Taketomi A, Shindoh M, Hida Y, Hida K. Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan. Sci Rep 2016; 6(1): 28039

[56] Knutson KL, Disis ML. Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother 2005; 54(8): 721–728

[57] Yoon NK, Maresh EL, Shen D, Elshimali Y, Apple S, Horvath S, Mah V, Bose S, Chia D, Chang HR, Goodglick L. Higher levels of GATA3 predict better survival in women with breast cancer. Hum Pathol 2010; 41(12): 1794–1801

[58] Erdag G, Schaefer JT, Smolkin ME, Deacon DH, Shea SM, Dengel LT, Patterson JW, Slingluff CL Jr. Immunotype and immunohistologic characteristics of tumor-infiltrating immune cells are associated with clinical outcome in metastatic melanoma. Cancer Res 2012; 72(5): 1070–1080

[59] Nedergaard BS, Ladekarl M, Nyengaard JR, Nielsen K. A comparative study of the cellular immune response in patients with stage IB cervical squamous cell carcinoma. Low numbers of several immune cell subtypes are strongly associated with relapse of disease within 5 years. Gynecol Oncol 2008; 108(1): 106–111

[60] Riemann D, Wenzel K, Schulz T, Hofmann S, Neef H, Lautenschläger C, Langner J. Phenotypic analysis of T lymphocytes isolated from non-small-cell lung cancer. Int Arch Allergy Immunol 1997; 114(1): 38–45

[61] Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund LT. Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res 2008; 14(16): 5220–5227

[62] Andreu P, Johansson M, Affara NI, Pucci F, Tan T, Junankar S, Korets L, Lam J, Tawfik D, DeNardo DG, Naldini L, de Visser KE, De Palma M, Coussens LM. FcRγ activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 2010; 17(2): 121–134

[63] de Visser KE, Korets LV, Coussens LM. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 2005; 7(5): 411–423

[64] Yuen GJ, Demissie E, Pillai S. B lymphocytes and cancer: a love-hate relationship. Trends Cancer 2016; 2(12): 747–757

[65] Ammirante M, Luo JL, Grivennikov S, Nedospasov S, Karin M. B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 2010; 464(7286): 302–305

[66] Luo JL, Tan W, Ricono JM, Korchynskyi O, Zhang M, Gonias SL, Cheresh DA, Karin M. Nuclear cytokine-activated IKKα controls prostate cancer metastasis by repressing Maspin. Nature 2007; 446(7136): 690–694

[67] Woo JR, Liss MA, Muldong MT, Palazzi K, Strasner A, Ammirante M, Varki N, Shabaik A, Howell S, Kane CJ, Karin M, Jamieson CA. Tumor infiltrating B-cells are increased in prostate cancer tissue. J Transl Med 2014; 12(1): 30

[68] Ou Z, Wang Y, Liu L, Li L, Yeh S, Qi L, Chang C. Tumor microenvironment B cells increase bladder cancer metastasis via modulation of the IL-8/androgen receptor (AR)/MMPs signals. Oncotarget 2015; 6(28): 26065–26078

[69] Rossi M, Young JW. Human dendritic cells: potent antigen-presenting cells at the crossroads of innate and adaptive immunity. J Immunol 2005; 175(3): 1373–1381

[70] Tran Janco JM, Lamichhane P, Karyampudi L, Knutson KL. Tumor-infiltrating dendritic cells in cancer pathogenesis. J Immunol 2015; 194(7): 2985–2991

[71] Ma Y, Shurin GV, Peiyuan Z, Shurin MR. Dendritic cells in the cancer microenvironment. J Cancer 2013; 4(1): 36–44

[72] Jochems C, Schlom J. Tumor-infiltrating immune cells and prognosis: the potential link between conventional cancer therapy and immunity. Exp Biol Med (Maywood) 2011; 236(5): 567–579

[73] Bekes EM, Schweighofer B, Kupriyanova TA, Zajac E, Ardi VC, Quigley JP, Deryugina EI. Tumor-recruited neutrophils and neutrophil TIMP-free MMP-9 regulate coordinately the levels of tumor angiogenesis and efficiency of malignant cell intravasation. Am J Pathol 2011; 179(3): 1455–1470

[74] Eruslanov EB, Bhojnagarwala PS, Quatromoni JG, Stephen TL, Ranganathan A, Deshpande C, Akimova T, Vachani A, Litzky L, Hancock WW, Conejo-Garcia JR, Feldman M, Albelda SM, Singhal S. Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer. J Clin Invest 2014; 124(12): 5466–5480

[75] Armulik A, Genové G, Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 2011; 21(2): 193–215

[76] O’Keeffe MB, Devlin AH, Burns AJ, Gardiner TA, Logan ID, Hirst DG, McKeown SR. Investigation of pericytes, hypoxia, and vascularity in bladder tumors: association with clinical outcomes. Oncol Res 2008; 17(3): 93–101

[77] Gee MS, Procopio WN, Makonnen S, Feldman MD, Yeilding NM, Lee WM. Tumor vessel development and maturation impose limits on the effectiveness of anti-vascular therapy. Am J Pathol 2003; 162(1): 183–193

[78] Yonenaga Y, Mori A, Onodera H, Yasuda S, Oe H, Fujimoto A, Tachibana T, Imamura M. Absence of smooth muscle actin-positive pericyte coverage of tumor vessels correlates with hematogenous metastasis and prognosis of colorectal cancer patients. Oncology 2005; 69(2): 159–166

[79] Sennino B, Falcón BL, McCauley D, Le T, McCauley T, Kurz JC, Haskell A, Epstein DM, McDonald DM. Sequential loss of tumor vessel pericytes and endothelial cells after inhibition of platelet-derived growth factor B by selective aptamer AX102. Cancer Res 2007; 67(15): 7358–7367

[80] Cooke VG, LeBleu VS, Keskin D, Khan Z, O’Connell JT, Teng Y, Duncan MB, Xie L, Maeda G, Vong S, Sugimoto H, Rocha RM, Damascena A, Brentani RR, Kalluri R. Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell 2012; 21(1): 66–81

[81] Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol 2012; 196(4): 395–406

[82] Naba A, Clauser KR, Lamar JM, Carr SA, Hynes RO. Extracellular matrix signatures of human mammary carcinoma identify novel metastasis promoters. eLife 2014; 3e01308

[83] Korpal M, Ell BJ, Buffa FM, Ibrahim T, Blanco MA, Celià-Terrassa T, Mercatali L, Khan Z, Goodarzi H, Hua Y, Wei Y, Hu G, Garcia BA, Ragoussis J, Amadori D, Harris AL, Kang Y. Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat Med 2011; 17(9): 1101–1108

[84] Andrén-Sandberg A. Pancreatic cancer: chemotherapy and radiotherapy. N Am J Med Sci 2011; 3(1): 1–12

[85] O’Reilly EA, Gubbins L, Sharma S, Tully R, Guang MH, Weiner-Gorzel K, McCaffrey J, Harrison M, Furlong F, Kell M, McCann A. The fate of chemoresistance in triple negative breast cancer (TNBC). BBA Clin 2015; 3: 257–275

[86] Sun Y, Campisi J, Higano C, Beer TM, Porter P, Coleman I, True L, Nelson PS. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med 2012; 18(9): 1359–1368

[87] DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, Gallagher WM, Wadhwani N, Keil SD, Junaid SA, Rugo HS, Hwang ES, Jirström K, West BL, Coussens LM. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 2011; 1(1): 54–67

[88] Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell 2015; 27(4): 462–472

[89] Takeuchi S, Baghdadi M, Tsuchikawa T, Wada H, Nakamura T, Abe H, Nakanishi S, Usui Y, Higuchi K, Takahashi M, Inoko K, Sato S, Takano H, Shichinohe T, Seino K, Hirano S. Chemotherapy-derived inflammatory responses accelerate the formation of immunosuppressive myeloid cells in the tissue microenvironment of human pancreatic cancer. Cancer Res 2015; 75(13): 2629–2640

[90] Zheng H, Bae Y, Kasimir-Bauer S, Tang R, Chen J, Ren G, Yuan M, Esposito M, Li W, Wei Y, Shen M, Zhang L, Tupitsyn N, Pantel K, King C, Sun J, Moriguchi J, Jun HT, Coxon A, Lee B, Kang Y. Therapeutic antibody targeting tumor- and osteoblastic niche-derived jagged1 sensitizes bone metastasis to chemotherapy. Cancer Cell 2017; 32(6): 731–747.e736

[91] Paris F, Fuks Z, Kang A, Capodieci P, Juan G, Ehleiter D, Haimovitz-Friedman A, Cordon-Cardo C, Kolesnick R. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 2001; 293(5528): 293–297

[92] Barker HE, Paget JT, Khan AA, Harrington KJ. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer 2015; 15(7): 409–425

[93] Moeller BJ, Cao Y, Li CY, Dewhirst MW. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 2004; 5(5): 429–441

[94] Laoui D, Van Overmeire E, De Baetselier P, Van Ginderachter JA, Raes G. Functional relationship between tumor-associated macrophages and macrophage colony-stimulating factor as contributors to cancer progression. Front Immunol 2014; 5: 489

[95] Zhou L, Zhang X, Li H, Niu C, Yu D, Yang G, Liang X, Wen X, Li M, Cui J. Validating the pivotal role of the immune system in low-dose radiation-induced tumor inhibition in Lewis lung cancer-bearing mice. Cancer Med 2018; 7(4): 1338–1348

[96] Smalley KS, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R, Van Belle P, Elder DE, Wang Y, Nathanson KL, Herlyn M. CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. Oncogene 2009; 28(1): 85–94

[97] Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther 2008; 7(10): 3129–3140

[98] Sprinzl MF, Reisinger F, Puschnik A, Ringelhan M, Ackermann K, Hartmann D, Schiemann M, Weinmann A, Galle PR, Schuchmann M, Friess H, Otto G, Heikenwalder M, Protzer U. Sorafenib perpetuates cellular anticancer effector functions by modulating the crosstalk between macrophages and natural killer cells. Hepatology 2013; 57(6): 2358–2368

[99] Ozao-Choy J, Ma G, Kao J, Wang GX, Meseck M, Sung M, Schwartz M, Divino CM, Pan PY, Chen SH. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res 2009; 69(6): 2514–2522

[100] Suh KJ, Sung JH, Kim JW, Han SH, Lee HS, Min A, Kang MH, Kim JE, Kim JW, Kim SH, Lee JO, Kim YJ, Lee KW, Kim JH, Bang SM, Im SA, Lee JS. EGFR or HER2 inhibition modulates the tumor microenvironment by suppression of PD-L1 and cytokines release. Oncotarget 2017; 8(38): 63901–63910

[101] Huang J, Wang L, Cong Z, Amoozgar Z, Kiner E, Xing D, Orsulic S, Matulonis U, Goldberg MS. The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a Brca1(−/−) murine model of ovarian cancer. Biochem Biophys Res Commun 2015; 463(4): 551–556

[102] Evans T, Matulonis U. PARP inhibitors in ovarian cancer: evidence, experience and clinical potential. Ther Adv Med Oncol 2017; 9(4): 253–267

[103] Fujishita T, Kojima Y, Kajino-Sakamoto R, Taketo MM, Aoki M. Tumor microenvironment confers mTOR inhibitor resistance in invasive intestinal adenocarcinoma. Oncogene 2017; 36(46): 6480–6489

[104] Jiao S, Xia W, Yamaguchi H, Wei Y, Chen MK, Hsu JM, Hsu JL, Yu WH, Du Y, Lee HH, Li CW, Chou CK, Lim SO, Chang SS, Litton J, Arun B, Hortobagyi GN, Hung MC. PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res 2017; 23(14): 3711–3720

[105] Pander J, Heusinkveld M, van der Straaten T, Jordanova ES, Baak-Pablo R, Gelderblom H, Morreau H, van der Burg SH, Guchelaar HJ, van Hall T. Activation of tumor-promoting type 2 macrophages by EGFR-targeting antibody cetuximab. Clin Cancer Res 2011; 17(17): 5668–5673

[106] Recouvreux S, Sampayo R, Bessone MI, Simian M. Microenvironment and endocrine resistance in breast cancer: friend or foe? World J Clin Oncol 2015; 6(6): 207–211

[107] Smith JA, Das A, Butler JT, Ray SK, Banik NL. Estrogen or estrogen receptor agonist inhibits lipopolysaccharide induced microglial activation and death. Neurochem Res 2011; 36(9): 1587–1593

[108] Keeton EK, Brown M. Cell cycle progression stimulated by tamoxifen-bound estrogen receptor-α and promoter-specific effects in breast cancer cells deficient in N-CoR and SMRT. Mol Endocrinol 2005; 19(6): 1543–1554

[109] Escamilla J, Schokrpur S, Liu C, Priceman SJ, Moughon D, Jiang Z, Pouliot F, Magyar C, Sung JL, Xu J, Deng G, West BL, Bollag G, Fradet Y, Lacombe L, Jung ME, Huang J, Wu L. CSF1 receptor targeting in prostate cancer reverses macrophage-mediated resistance to androgen blockade therapy. Cancer Res 2015; 75(6): 950–962

[110] Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell 2010; 141(1): 39–51

[111] De Palma M, Lewis CE. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 2013; 23(3): 277–286

[112] Liu Y, Fan L, Wang Y, Li P, Zhu J, Wang L, Zhang W, Zhang Y, Huang G. Tumor-associated macrophages promote tumor cell proliferation in nasopharyngeal NK/T-cell lymphoma. Int J Clin Exp Pathol 2014; 7(9): 5429–5435

[113] Yang Y, Bai Y, He Y, Zhao Y, Chen J, Ma L, Pan Y, Hinten M, Zhang J, Karnes RJ, Kohli M, Westendorf JJ, Li B, Zhu R, Huang H, Xu W. PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-resistant prostate cancer. Clin Cancer Res 2018; 24(4): 834–846

[114] Wang D, DuBois RN. Immunosuppression associated with chronic inflammation in the tumor microenvironment. Carcinogenesis 2015; 36(10): 1085–1093

[115] Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 2015; 27(4): 450–461

[116] Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol 2016; 39(1): 98–106

[117] Chambers CA, Kuhns MS, Egen JG, Allison JP. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 2001; 19(1): 565–594

[118] Collins AV, Brodie DW, Gilbert RJ, Iaboni A, Manso-Sancho R, Walse B, Stuart DI, van der Merwe PA, Davis SJ. The interaction properties of costimulatory molecules revisited. Immunity 2002; 17(2): 201–210

[119] Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005; 25(21): 9543–9553

[120] Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26(1): 677–704

[121] He J, Hu Y, Hu M, Li B. Development of PD-1/PD-L1 pathway in tumor immune microenvironment and treatment for non-small cell lung cancer. Sci Rep 2015; 5(1): 13110

[122] Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996; 271(5256): 1734–1736

[123] Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol 2015; 33(17): 1974–1982

[124] Maker AV, Attia P, Rosenberg SA. Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J Immunol 2005; 175(11): 7746–7754

[125] Quezada SA, Peggs KS, Curran MA, Allison JP. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest 2006; 116(7): 1935–1945

[126] Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000; 192(2): 303–310

[127] Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, Davis T, Henry-Spires R, MacRae S, Willman A, Padera R, Jaklitsch MT, Shankar S, Chen TC, Korman A, Allison JP, Dranoff G. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA 2003; 100(8): 4712–4717

[128] Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK, Iyer AK. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol 2017; 8: 561

[129] Riaz N, Havel JJ, Makarov V, Desrichard A, Urba WJ, Sims JS, Hodi FS, Martin-Algarra S, Mandal R, Sharfman WH, Bhatia S, Hwu WJ, Gajewski TF, Slingluff CL Jr, Chowell D, Kendall SMChang H, Shah R, Kuo F, Morris LGT, Sidhom JW, Schneck JP, Horak CE, Weinhold N, Chan TA. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 2017; 171(4): 934–949.e915

[130] Lichty BD, Breitbach CJ, Stojdl DF, Bell JC. Going viral with cancer immunotherapy. Nat Rev Cancer 2014; 14(8): 559–567

[131] Mastrangelo MJ, Maguire HC Jr, Eisenlohr LC, Laughlin CE, Monken CE, McCue PA, Kovatich AJ, Lattime EC. Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma. Cancer Gene Ther 1999; 6(5): 409–422

[132] de Vries CR, Kaufman HL, Lattime EC. Oncolytic viruses: focusing on the tumor microenvironment. Cancer Gene Ther 2015; 22(4): 169–171

[133] Park BH, Hwang T, Liu TC, Sze DY, Kim JS, Kwon HC, Oh SY, Han SY, Yoon JH, Hong SH, Moon A, Speth K, Park C, Ahn YJ, Daneshmand M, Rhee BG, Pinedo HM, Bell JC, Kirn DH. Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. Lancet Oncol 2008; 9(6): 533–542

[134] Kaufman HL, DeRaffele G, Divito J, Hörig H, Lee D, Panicali D, Voulo M. A phase I trial of intralesional rV-Tricom vaccine in the treatment of malignant melanoma. Hum Gene Ther 2001; 12(11): 1459–1480

[135] Kaufman HL, Kim DW, DeRaffele G, Mitcham J, Coffin RS, Kim-Schulze S. Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Ann Surg Oncol 2010; 17(3): 718–730

[136] Kudo-Saito C, Schlom J, Hodge JW. Intratumoral vaccination and diversified subcutaneous/ intratumoral vaccination with recombinant poxviruses encoding a tumor antigen and multiple costimulatory molecules. Clin Cancer Res 2004; 10(3): 1090–1099

[137] de Vries CR, Monken CE, Lattime EC. The addition of recombinant vaccinia HER2/neu to oncolytic vaccinia-GMCSF given into the tumor microenvironment overcomes MDSC-mediated immune escape and systemic anergy. Cancer Gene Ther 2015; 22(3): 154–162

[138] Gulley JL, Heery CR, Madan RA, Walter BA, Merino MJ, Dahut WL, Tsang KY, Schlom J, Pinto PA. Phase I study of intraprostatic vaccine administration in men with locally recurrent or progressive prostate cancer. Cancer Immunol Immunother 2013; 62(9): 1521–1531

[139] Madan RA, Heery CR, Gulley JL. Poxviral-based vaccine elicits immunologic responses in prostate cancer patients. Oncoimmunology 2014; 3e28611

[140] Anassi E, Ndefo UA. Sipuleucel-T (provenge) injection: the first immunotherapy agent (vaccine) for hormone-refractory prostate cancer. P T 2011; 36(4): 197–202

[141] Ojha T, Pathak V, Shi Y, Hennink WE, Moonen CTW, Storm G, Kiessling F, Lammers T. Pharmacological and physical vessel modulation strategies to improve EPR-mediated drug targeting to tumors. Adv Drug Deliv Rev 2017; 119: 44–60

[142] Gao W, Li S, Liu Z, Sun Y, Cao W, Tong L, Cui G, Tang B. Targeting and destroying tumor vasculature with a near-infrared laser-activated “nanobomb” for efficient tumor ablation. Biomaterials 2017; 139: 1–11

[143] Kunjachan S, Detappe A, Kumar R, Ireland T, Cameron L, Biancur DE, Motto-Ros V, Sancey L, Sridhar S, Makrigiorgos GM, Berbeco RI. Nanoparticle mediated tumor vascular disruption: a novel strategy in radiation therapy. Nano Lett 2015; 15(11): 7488–7496

[144] Miao L, Wang Y, Lin CM, Xiong Y, Chen N, Zhang L, Kim WY, Huang L. Nanoparticle modulation of the tumor microenvironment enhances therapeutic efficacy of cisplatin. J Control Release 2015; 217: 27–41

[145] Hu K, Miao L, Goodwin TJ, Li J, Liu Q, Huang L. Quercetin remodels the tumor microenvironment to improve the permeation, retention, and antitumor effects of nanoparticles. ACS Nano 2017; 11(5): 4916–4925

[146] Miao L, Liu Q, Lin CM, Luo C, Wang Y, Liu L, Yin W, Hu S, Kim WY, Huang L. Targeting tumor-associated fibroblasts for therapeutic delivery in desmoplastic tumors. Cancer Res 2017; 77(3): 719–731

[147] Lee S, Han H, Koo H, Na JH, Yoon HY, Lee KE, Lee H, Kim H, Kwon IC, Kim K. Extracellular matrix remodeling in vivo for enhancing tumor-targeting efficiency of nanoparticle drug carriers using the pulsed high intensity focused ultrasound. J Control Release 2017; 263: 68–78

[148] Zhou H, Fan Z, Deng J, Lemons PK, Arhontoulis DC, Bowne WB, Cheng H. Hyaluronidase embedded in nanocarrier PEG shell for enhanced tumor penetration and highly efficient antitumor efficacy. Nano Lett 2016; 16(5): 3268–3277

[149] Gong H, Chao Y, Xiang J, Han X, Song G, Feng L, Liu J, Yang G, Chen Q, Liu Z. Hyaluronidase to enhance nanoparticle-based photodynamic tumor therapy. Nano Lett 2016; 16(4): 2512–2521

[150] Shay G, Lynch CC, Fingleton B. Moving targets: emerging roles for MMPs in cancer progression and metastasis. Matrix Biol 2015; 44– 46: 200–206

[151] Hu XX, He PP, Qi GB, Gao YJ, Lin YX, Yang C, Yang PP, Hao H, Wang L, Wang H. Transformable nanomaterials as an artificial extracellular matrix for inhibiting tumor invasion and metastasis. ACS Nano 2017; 11(4): 4086–4096

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Minhong Shen and Yibin Kang declare no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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