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Enabling T Cell Recruitment to Tumours as a Strategy for Improving Adoptive T Cell Therapy

European Oncology & Haematology, 2017;13(1):66–73 DOI:


Immunotherapy has successfully been implemented as the standard of care in a number of oncologic indications. A hallmark of cancer immunotherapy is the successful activation of T cells against cancer cells, leading to unparalleled efficacy for some tumour entities. However, current approved approaches are not specific, limiting both their activity and their safety. A more tailored way of using the therapeutic potential of T cells is adoptive T cell therapy, which encompasses ex vivo T cell manipulation and reinfusion to patients suffering from cancer. In haematologic malignancies such as acute lymphatic leukaemia of the B cell lineage, T cells modified with a chimeric antigen receptor against the B cell lineage antigen CD19 induce remissions in a high proportion of patients. In contrast, patients suffering from advanced solid tumours have shown little benefit from cell-based approaches. This is partly due to limited access of T cells to the tumour tissue, consequently restricting T cell activity. In this review, we focus on the limitations of T cell trafficking towards solid tumours. We summarise the existing knowledge on lymphocyte migration to understand how this pathway may be used to open therapeutic approaches for a broader range of indications. We also review new strategies targeting the tumour site that aid naturally occurring or gene-engineered T cells to migrate to solid tumours. Finally, we discuss how guiding T cells towards the tumour might contribute in harnessing their full cytolytic potential.
Keywords: Adoptive T cell therapy, homing, immune supression, antigen recognition, CAR T cells, TCR T cells, TILs, chemokine receptors
Disclosure: Bruno Cadilha, Klara Dorman, Felicitas Rataj, Stefan Endres and Sebastian Kobold have nothing to declare in relation to this article. No funding was received in the publication of this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.
Acknowledgments: This study was supported by grants from the Wilhelm Sander Stiftung (grant number 2014.018.1 to SE and SK), the international doctoral program ‘i-Target: Immunotargeting of cancer’ funded by the Elite Network of Bavaria (to SK and SE), the Melanoma Research Alliance (grant number N269626 to SE and 409510 to SK), the Marie-Sklodowska-Curie ‘Training Network for the Immunotherapy of Cancer (IMMUTRAIN)’ funded by the H2020 program of the European Union (to SE and SK), the Else Kröner-Fresenius-Stiftung (to SK), the German Cancer Aid (to SK), the Ernst-Jung-Stiftung (to SK), by LMU Munich‘s Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative (to SE and SK).
AuthorshipAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
Received: February 24, 2017 Accepted: May 02, 2017
Correspondence: Sebastian Kobold, Division of Clinical Pharmacology, Klinikum der Universität München, Lindwurmstrasse 2a, 80337 Munich, Germany. E:

Cancer immunotherapy has come of age and has successfully been implemented as the standard of care in a number of oncologic indications.1 Antibodies targeting cancer-associated antigens on the tumour cell, such as CD20, constituted the first wave of immunotherapies leading to the first approval of an antibody for cancer therapy. In 1997, rituximab, an anti-CD20 antibody was approved for the treatment of high-grade B cell lymphomas.2 Twenty-one compounds with similar tumour-targeted concepts have been approved for cancer treatment in Europe in the meantime. Despite being thought that the mode of action of such antibodies mainly relied on a direct antitumoural attack, emerging evidence suggests a contribution of the innate and adaptive immune system.3–6 Tumour-targeted monoclonal antibodies are now mainly considered as a passive immunotherapy.7–10

More recently, a paradigm change has occurred, moving the focus of therapeutic endeavours away from the cancer cell to effector components of the immune system, mainly T cells.11 Preclinical and clinical evidence have now demonstrated that allowing T cell activation results in antitumoural activity without bona fide tumour-targeting. Antibodies targeting checkpoint inhibitors on T cells such as, programmed death receptor 1 (PD-1) or cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), reverse T cell anergy and lead to T cell-mediated remissions. Such antibodies can induce unparalleled activity in patients with advanced stage disease or having failed multiple lines of therapy, even in entities classically deemed nonsuitable for immunotherapies. As a consequence, approvals for cancer immunotherapies now span a broad scope of indications including acute lymphatic leukaemia (ALL), melanoma, nonsmall cell lung cancer, kidney cancer, Hodgkin lymphoma and head and neck cancer.12–17 A major limitation of the approach is its unspecific nature of T cell targeting, resulting in severe side effects.18–20 Strategies allowing for a more directed and specific therapeutic use of T cells may have advantages in terms of specificity and efficacy.

Adoptive T cell therapy (ACT) is a strategy that directly employs T cells with therapeutic intention against cancer.21 T cells can be isolated from a patient’s blood or tumour samples. Those derived from the tumour are also known as tumour-infiltrating lymphocytes (TILs).21,22 Isolation is followed by in vitro expansion and manipulation, and then reinfusion into the patient.21 ACT protocols that employ TILs are generally accompanied by preconditioning of the patients prior to treatment. In most cases, however, TILs cannot be isolated due to the lack of accessible tumour tissue or lack of tumour-specific T cells.23 Through genetic engineering, T cells can be rendered specific for a given target. This process encompasses the transduction or transient transfection with defined natural or synthetic genes. Two major strategies to engineer tumourspecific T cells have emerged: T cell receptors (TCRs)24–26 specific for a peptide presented in a major histocompatibility complex-dependent manner, and chimeric antigen receptors (CARs)27–30 which are synthetic T cell activating receptors targeting cell surface antigens. TCRs correspond to the natural molecule found in any T cell with modifications to enhance their biochemical and functional properties, while CARs are constituted of the variable fragment of an antibody fused to T cell activating CD3 zeta chain and co-stimulatory domains (overview in Figure 1). TILs, TCR and CAR T cells are currently being tested in various tumour indications in clinical trials (Figure 2).

1. Kobold S, Duewell P, Schnurr M, et al., Immunotherapy in tumors, Dtsch Arztebl Int, 2015;112:809–15.
2. Dotan E, Aggarwal C, Smith MR, Impact of rituximab (rituxan) on the treatment of B-cell non-Hodgkin’s lymphoma, P T, 2010;353:148–57.
3. Smith MR, Rituximab (monoclonal anti-CD20 antibody): Mechanisms of action and resistance, Oncogene, 2003;22:7359–68.
4. Boross P, Leusen JHW, Mechanisms of action of CD20 antibodies, Am J Cancer Res, 2012;2:676–90.
5. Scott AM, Wolchok JD, Old LJ, Antibody therapy of cancer, Nat Rev Cancer, 2012;12:278–87.
6. Tumeh PC, Harview CL, Yearley JH, et al., PD-1 blockade induces responses by inhibiting adaptive immune resistance, Nature, 2014;515:568–71.
7. Greenberg PD, Adoptive T cell therapy of tumors: mechanisms operative in the recognition and elimination of tumor cells, Adv Immunol, 1991;49:281–355.
8. Cheever MA, Chen W, Therapy with cultured T cells: principles revisited, Immunol Rev, 1997;157:177–94.
9. Kalos M, June CH, Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology, Immunity, 2013;39:49–60.
10. Restifo NP, Smyth MJ, Snyder A, Acquired resistance to immunotherapy and future challenges, Nat Rev Cancer, 2016;16:121–6.
11. Shekarian T, Valsesia-Wittmann S, Caux C, Marabelle A, Paradigm shift in oncology: Targeting the immune system rather than cancer cells, Mutagenesis, 2015;30:205–11.
12. Hodi FS, O’Day SJ, McDermott DF, et al., Improved survival with ipilimumab in patients with metastatic melanoma, N Engl J Med, 2010;363:711–23.
13. Topalian SL, Hodi FS, Brahmer JR, Safety, activity, and immune correlates of anti-PD-1 antibody in cancer, N Engl J Med, 2012;366:2443–54.
14. Powles T, Eder JP, Fine GD, et al., MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer, Nature, 2014;515:558–62.
15. Ansell SM, Lesokhin AM, Borrello I, et al., PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma, N Engl J Med, 2015;372:311–9.
16. Brahmer J, Reckamp KL, Baas P, et al., Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer, N Engl J Med, 2015;373:123–35.
17. Hamanishi J, Mandai M, Ikeda T, et al., Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer, J Clin Oncol, 2015;33:4015–22.
18. Azoury SC, Straughan DM, Shukla V, Immune checkpoint inhibitors for cancer therapy: Clinical efficacy and safety, Curr Cancer Drug Targets, 2015;15:452–62.
19. La-Beck NM, Jean GW, Huynh C, et al., Immune checkpoint inhibitors: New insights and current place in cancer therapy, Pharmacotherapy, 2015;35:963–76.
20. Dadu R, Zobniw C, Diab A, Managing adverse events with immune checkpoint agents, Cancer J, 2016;22:121–9.
21. Rosenberg SA, Restifo NP, Adoptive cell transfer as personalized immunotherapy for human cancer, Science, 2015;348:62–8.
22. Rosenberg SA, Spiess P, Lafreniere R, A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes, Science, 1986;233:1318–21.
23. Whiteside TL, Jost LM, Herberman RB, Tumor-infiltrating lymphocytes. Potential and limitations to their use for cancer therapy, Crit Rev Oncol Hematol, 1992;12:25–47.
24. Ahmadi M, King JW, Xue SA, et al., CD3 limits the efficacy of TCR gene therapy in vivo, Blood, 2011;118:3528–37.
25. Abate-Daga D, Hanada K, Davis JL, et al., Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes, Blood, 2013;122:1399–410.
26. Palmer DC, Guittard GC, Franco Z, et al., Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance, J Exp Med, 2015;212:2095–113.
27. Eshhar Z, Waks T, Gross G, Schindler DG, Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors, Proc Natl Acad Sci U S A, 1993;90:720–4.
28. Kershaw MH, Westwood JA, Darcy PK, Gene-engineered T cells for cancer therapy, Nat Rev Cancer, 2013;13:525–41.
29. Frigault MJ, Lee J, Basil MC, et al., Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells, Cancer Immunol Res, 2015;3:356–67.
30. Long AH, Haso WM, Shern JF, et al., 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors, Nat Med, 2015;21:581–90.
31. Kochenderfer JN, Wilson WH, Janik JE, et al., Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19, Blood, 2010;116:4099–102.
32. Klebanoff CA, Rosenberg SA, Restifo NP, Prospects for geneengineered T cell immunotherapy for solid cancers, Nat Med, 2016;22:26–36.
33. Rosenberg SA, Yang JC, Sherry RM, et al., Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy, Clin Cancer Res, 2011;17:4550–7.
34. Junker N, Kvistborg P, Kollgaard T, et al., Tumor associated antigen specific T-cell populations identified in ex vivo expanded TIL cultures, Cell Immunol, 2012;273:1–9.
35. Hadrup S, Donia M, Thor Straten P, Effector CD4 and CD8 T cells and their role in the tumor microenvironment, Cancer Microenviron, 2013;6:123–33.
36. Lu YC, Yao X, Crystal JS, et al., Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions, Clin Cancer Res, 2014;20:3401–10.
37. Morgan RA, Chinnasamy N, Abate-Daga D, Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy, J Immunother, 2013;36:133–51.
38. Linette GP, Stadtmauer EA, Maus MV, et al., Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma, Blood, 2013;122:863–71.
39. Parkhurst MR, Yang JC, Langan RC, et al., T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis, Mol Ther, 2011;19:620–6.
40. Robbins PF, Morgan RA, Feldman SA, et al., Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NYESO- 1, J Clin Oncol, 2011;29:917–24.
41. Chodon T, Comin-Anduix B, Chmielowski B, Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma, Clin Cancer Res, 2014;20:2457–65.
42. Kageyama S, Ikeda H, Miyahara Y, et al., Adoptive transfer of MAGE-A4 T-cell receptor gene-transduced lymphocytes in patients with recurrent esophageal cancer, Clin Cancer Res, 2015;21:2268–77.
43. Robbins PF, Kassim SH, Tran TLN, et al., A pilot trial using lymphocytes genetically engineered with an NY-ESO-1–reactive T-cell receptor: Long-term follow-up and correlates with response, Clin Cancer Res, 2015;21:1019–27.
44. Maude SL, Frey N, Shaw PA, et al., Chimeric antigen receptor T cells for sustained remissions in leukemia, N Engl J Med, 2014;371:1507–17.
45. Turtle CJ, Hanafi LA, Berger C, et al., CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients, J Clin Invest, 2016;126:2123–38.
46. Kochenderfer JN, Dudley ME, Kassim SH, et al., Chemotherapyrefractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor, J Clin Oncol, 2015;33:540–9.
47. Brentjens RJ, Riviere I, Park JH, et al., Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias, Blood, 2011;118:4817–28.
48. Davila ML, Riviere I, Wang X, Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia, Sci Transl Med, 2014;6:224ra25.
49. Brudno JN, Kochenderfer JN, Toxicities of chimeric antigen receptor T cells: Recognition and management, Blood, 2016;127:3321–30.
50. Morgan RA, Yang JC, Kitano M, et al., Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2, Mol Ther, 2010;18:843–51.
51. Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ, Toxicity and management in CAR T-cell therapy, Mol Ther Oncolytics, 2016;3:16011.
52. Fesnak AD, June CH, Levine BL, Engineered T cells: The promise and challenges of cancer immunotherapy, Nat Rev Cancer, 2016;16:566–81.
53. Kadambi A, Mouta Carreira C, Yun CO, et al., Vascular endothelial growth factor (VEGF)-C differentially affects tumor vascular function and leukocyte recruitment, Cancer Res, 2001;61:2404–8.
54. Musha H, Ohtani H, Mizoi T, et al., Selective infiltration of CCR5+CXCR3+ T lymphocytes in human colorectal carcinoma, Int J Cancer, 2005;116:949–56.
55. Harlin H, Meng Y, Peterson AC, et al., Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment, Cancer Res, 2009;69:3077–85.
56. Cairns RA, Harris IS, Mak TW, Regulation of cancer cell metabolism, Nat Rev Cancer, 2011;11:85–95.
57. Feig C, Jones JO, Kraman M, et al., Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer, Proc Natl Acad Sci U S A, 2013;110:20212–7.
58. Mulligan AM, Raitman I, Feeley L, et al., Tumoral lymphocytic infiltration and expression of the chemokine CXCL10 in Breast Cancers from the Ontario Familial Breast Cancer Registry, Clin Cancer Res, 2013;19:336–46.
59. Yewdell JW, Bennink JR, Cell biology of antigen processing and presentation to major histocompatibility complex class I molecule-restricted T lymphocytes, Adv Immunol, 1992;52:1–123.
60. Restifo NP, Kawakami Y, Marincola F, et al., Molecular mechanisms used by tumors to escape immune recognition: Immunogenetherapy and the cell biology of major histocompatibility complex class I, J Immunother Emphasis Tumor Immunol, 1993;14:182–90.
61. Pardoll DM, The blockade of immune checkpoints in cancer immunotherapy, Nat Rev Cancer, 2012;12:252–64.
62. Zhao Y, Bennett AD, Zheng Z, et al., High-affinity TCRs generated by phage display provide CD4+ T cells with the ability to recognize and kill tumor cell lines, J Immunol, 2007;179:5845–54.
63. Vigneron N, Stroobant V, Van den Eynde BJ, van der Bruggen P, Database of T cell-defined human tumor antigens: The 2013 update, Cancer Immun, 2013;13:15.
64. Maher J, Brentjens RJ, Gunset G, et al., Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCR[zeta]/CD28 receptor, Nat Biotech, 2002;20:70–5.
65. Moeller M, Haynes NM, Trapani JA, et al., A functional role for CD28 costimulation in tumor recognition by single-chain receptor-modified T cells, Cancer Gene Ther, 2004;11:371–9.
66. Guest RD, Hawkins RE, Kirillova N, et al., The role of extracellular spacer regions in the optimal design of chimeric immune receptors: evaluation of four different scFvs and antigens, J Immunother, 2005;28:203–11.
67. Carpenito C, Milone MC, Hassan R, et al., Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains, Proc Natl Acad Sci U S A, 2009;106:3360–5.
68. Zhao Y, Wang QJ, Yang S, et al., A herceptin-based chimeric antigen receptor with modified signaling domains leads to enhanced survival of transduced T lymphocytes and antitumor activity, J Immunol, 2009;183:5563–74.
69. Bridgeman JS, Hawkins RE, Hombach AA, et al., Building better chimeric antigen receptors for adoptive T cell therapy, Curr Gene Ther, 2010;10:77–90.
70. Zhong XS, Matsushita M, Plotkin J, et al., Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cellmediated tumor eradication, Mol Ther, 2010;18:413–20.
71. Cheadle EJ, Sheard V, Hombach AA, et al., Chimeric antigen receptors for T-cell based therapy, Methods Mol Biol, 2012;907:645–66.
72. Duong CP, Westwood JA, Yong CS, et al., Engineering T cell function using chimeric antigen receptors identified using a DNA library approach, PLoS One, 2013;8:e63037.
73. Kunii N, Zhao Y, Jiang S, et al., Enhanced function of redirected human T cells expressing linker for activation of T cells that is resistant to ubiquitylation, Hum Gene Ther, 2013;24:27–37.
74. Kobold S, Grassmann S, Chaloupka M, et al., Impact of a new fusion receptor on PD-1-mediated immunosuppression in adoptive T cell therapy, J Natl Cancer Inst, 2015;107:pii:djv 146.
75. Johnson LA, June CH, Driving gene-engineered T cell immunotherapy of cancer, Cell Res, 2017;27:38–58.
76. Yong CSM, Dardalhon V, Devaud C, et al., CAR T-cell therapy of solid tumors, Immunol Cell Biol, 2017;95:356–63.
77. Slaney CY, Kershaw MH, Darcy PK, Trafficking of T cells into tumors, Cancer Res, 2014;74:7168–74.
78. Kmiecik J, Poli A, Brons NH, et al., Elevated CD3+ and CD8+ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level, J Neuroimmunol, 2013;264:71–83.
79. Galon J, Costes A, Sanchez-Cabo F, et al., Type, density, and location of immune cells within human colorectal tumors predict clinical outcome, Science, 2006;313:1960–4.
80. Kim ST, Jeong H, Woo OH, et al., Tumor-infiltrating lymphocytes, tumor characteristics, and recurrence in patients with early breast cancer, Am J Clin Oncol, 2013;36:224–31.
81. Piersma SJ, Jordanova ES, van Poelgeest MI, et al. High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer, Cancer Res, 2007;67:354–61.
82. Galon J, Mlecnik B, Bindea G, et al., Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours, J Pathol, 2014;232:199–209.
83. von Andrian UH, Chambers JD, McEvoy LM, et al., Two-step model of leukocyte-endothelial cell interaction in inflammation: Distinct roles for LECAM-1 and the leukocyte beta 2 integrins in vivo, Proc Natl Acad Sci U S A, 1991;88:7538–42.
84. von Andrian UH, Hansell P, Chambers JD, et al., L-selectin function is required for beta 2-integrin-mediated neutrophil adhesion at physiological shear rates in vivo, Am J Physiol, 1992;263:H1034–44.
85. Gallatin WM, Weissman IL, Butcher EC, A cell-surface molecule involved in organ-specific homing of lymphocytes, Nature, 1983;304:30–4.
86. Bargatze RF, Butcher EC, Rapid G protein-regulated activation event involved in lymphocyte binding to high endothelial venules, J Exp Med, 1993;178:367–72.
87. Campbell JJ, Hedrick J, Zlotnik A, et al., Chemokines and the arrest of lymphocytes rolling under flow conditions, Science, 1998;279:381–4.
88. von Andrian UH, Mackay CR, T-cell function and migration. Two sides of the same coin, N Engl J Med, 2000;343:1020–34.
89. Ley K, Laudanna C, Cybulsky MI, Nourshargh S, Getting to the site of inflammation: The leukocyte adhesion cascade updated, Nat Rev Immunol, 2007;7:678–89.
90. Godfrey DI, Zlotnik A, Control points in early T-cell development, Immunol Today, 1993;14:547–53.
91. Berger EA, HIV entry and tropism: the chemokine receptor connection, Aids, 1997;11:S3–16.
92. Luster AD, Chemokines-chemotactic cytokines that mediate inflammation, N Engl J Med, 1998;338:436–45.
93. Kim CH, Broxmeyer HE, Chemokines: Signal lamps for trafficking of T and B cells for development and effector function, J Leukoc Biol, 1999;65:6–15.
94. Kiefer F, Siekmann AF, The role of chemokines and their receptors in angiogenesis, Cell Mol Life Sci, 2011;68:2811–30.
95. Nomiyama H, Hieshima K, Osada N, et al., Extensive expansion and diversification of the chemokine gene family in zebrafish: Identification of a novel chemokine subfamily CX, BMC Genomics, 2008;9: 222.
96. Zlotnik A, Yoshie O, The chemokine superfamily revisited, Immunity, 2012;36:705–16.
97. Cabrera-Vera TM, Vanhauwe J, Thomas TO, et al., Insights into G protein structure, function, and regulation, Endocr Rev, 2003;24:765–81.
98. Johnson Z, Power CA, Weiss C, et al., Chemokine inhibition - why, when, where, which and how?, Biochem Soc Trans, 2004;32:366–77.
99. Goldsmith ZG, Dhanasekaran DN, G protein regulation of MAPK networks, Oncogene, 2007;26:3122–42.
100. Barretina J, Caponigro G, Stransky N, The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity, Nature, 2012;483:603–7.
101. Atretkhany KSN, Drutskaya MS, Nedospasov SA, et al., Chemokines, cytokines and exosomes help tumors to shape inflammatory microenvironment, Pharmacol Ther, 2016;168:98–112.
102. Curiel TJ, Coukos G, Zou L, et al., Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival, Nat Med, 2004;10:942–9.
103. Facciabene A, Peng X, Hagemann IS, et al., Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells, Nature, 2011;475:226–30.
104. Rapp M, Grassmann S, Chaloupka M, et al., C-C chemokine receptor type-4 transduction of T cells enhances interaction with dendritic cells, tumor infiltration and therapeutic efficacy of adoptive T cell transfer, Oncoimmunology, 2016;5:e1105428.
105. Bailey C, Negus R, Morris A, et al., Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer, Clin Exp Metastasis, 2007;24:121–30.
106. Hong M, Puaux AL, Huang C, et al., Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T-cell infiltration and tumor control, Cancer Res, 2011;71:6997–7009.
107. Baj-Krzyworzeka M, Weglarczyk K, Mytar B, et al., Tumourderived microvesicles contain interleukin-8 and modulate production of chemokines by human monocytes, Anticancer Res, 2011;31:1329–35.
108. Mantovani A, Sica A, Sozzani S, et al., The chemokine system in diverse forms of macrophage activation and polarization, Trends Immunol, 2004;25:677–86.
109. Qian BZ, Pollard JW, Macrophage diversity enhances tumor progression and metastasis, Cell, 2010;141:39–51.
110. Aldinucci D, Colombatti A, The inflammatory chemokine CCL5 and cancer progression, Mediators Inflamm, 2014;2014:292–376.
111. Vaday GG, Peehl DM, Kadam PA, Lawrence DM, Expression of CCL5 (RANTES) and CCR5 in prostate cancer, Prostate, 2006;66:124–34.
112. Kitamura T, Kometani K, Hashida H, et al., SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion, Nat Genet, 2007;39:467–75.
113. Chow MT, Luster AD, Chemokines in cancer, Cancer Immunol Res, 2014;2:1125–31.
114. Das S, Sarrou E, Podgrabinska S, et al., Tumor cell entry into the lymph node is controlled by CCL1 chemokine expressed by lymph node lymphatic sinuses, J Exp Med, 2013;210:1509–28.
115. Strieter RM, Burdick MD, Gomperts BN, et al., CXC chemokines in angiogenesis, Cytokine Growth Factor Rev, 2005;16:593–609.
116. Nagasawa T, Hirota S, Tachibana K, et al., Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1, Nature, 1996;382:635–8.
117. Tachibana K, Hirota S, Iizasa H, et al., The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract, Nature, 1998;393:591–4.
118. Devaud C, John LB, Westwood JA, et al., Immune modulation of the tumor microenvironment for enhancing cancer immunotherapy, Oncoimmunology, 2013;2:e25961.
119. Roselli M, Cereda V, di Bari MG, et al., Effects of conventional therapeutic interventions on the number and function of regulatory T cells, Oncoimmunology, 2013;2:e27025.
120. Oelkrug C, Ramage JM, Enhancement of T cell recruitment and infiltration into tumours, Clin Exp Immunol, 2014;178:1–8.
121. Clark-Lewis I, Schumacher C, Baggiolini M, Moser B, Structure-activity relationships of interleukin-8 determined using chemically synthesized analogs. Critical role of NH2- terminal residues and evidence for uncoupling of neutrophil chemotaxis, exocytosis, and receptor binding activities, J Biol Chem, 1991;266:23128–34.
122. Zhang Y, Rollins BJ, A dominant negative inhibitor indicates that monocyte chemoattractant protein 1 functions as a dimer, Mol Cell Biol, 1995;5:4851–5.
123. Gong JH, Uguccioni M, Dewald B, et al., RANTES and MCP-3 antagonists bind multiple chemokine receptors, J Biol Chem, 1996;271:10521–7.
124. Koga M, Kai H, Egami K, et al., Mutant MCP-1 therapy inhibits tumor angiogenesis and growth of malignant melanoma in mice, Biochem Biophys Res Commun, 2008;365:279–84.
125. Klarenbeek A, Maussang D, Blanchetot C, et al., Targeting chemokines and chemokine receptors with antibodies, Drug Discov Today, 2012;9:e237–44.
126. Proudfoot AEI, Bonvin P, Power CA, Targeting chemokines: Pathogens can, why can’t we?, Cytokine, 2015;74:259–67.
127. Peng W, Liu C, Xu C, et al., PD-1 blockade enhances T-cell migration to tumors by elevating IFN-gamma inducible chemokines, Cancer Res, 2012;72:5209–18.
128. Fluhr H, Seitz T, Zygmunt M, Heparins modulate the IFNgamma- induced production of chemokines in human breast cancer cells, Breast Cancer Res Treat, 2013;137:109–18.
129. Hoelzinger DB, Smith SE, Mirza N, et al., Blockade of CCL1 inhibits T regulatory cell suppressive function enhancing tumor immunity without affecting T effector responses, J Immunol, 2010;184:6833–42.
130. Spear P, Barber A, Sentman CL, Collaboration of chimeric antigen receptor (CAR)-expressing T cells and host T cells for optimal elimination of established ovarian tumors, Oncoimmunology, 2013;2:e23564.
131. Guirnalda P, Wood L, Goenka R, et al., Interferon gammainduced intratumoral expression of CXCL9 alters the local distribution of T cells following immunotherapy with Listeria monocytogenes, Oncoimmunology, 2013;2:e25752.
132. Tannenbaum CS, Tubbs R, Armstrong D, et al., The CXC chemokines IP-10 and Mig are necessary for IL-12-mediated regression of the mouse RENCA tumor, J Immunol, 1998;161:927–32.
133. Iezzi G, Karjalainen K, Lanzavecchia A, The duration of antigenic stimulation determines the fate of naive and effector T cells, Immunity, 1998;8:89–95.
134. Hou S, Hyland L, Ryan KW, et al., Virus-specific CD8+ T-cell memory determined by clonal burst size, Nature, 1994;369:652–4.
135. Busch DH, Pilip IM, Vijh S, Pamer EG, Coordinate regulation of complex T cell populations responding to bacterial infection, Immunity, 1998;8:353–62.
136. Bachmann MF, Barner M, Viola A, Kopf M, Distinct kinetics of cytokine production and cytolysis in effector and memory T cells after viral infection, Eur J Immunol, 1999;29:291–9.
137. Veiga-Fernandes H, Walter U, Bourgeois C, et al., Response of naive and memory CD8+ T cells to antigen stimulation in vivo, Nat Immunol, 2000;1:47–53.
138. Sallusto F, Lenig D, Forster R, et al., Two subsets of memory T lymphocytes with distinct homing potentials and effector functions, Nature, 1999;401:708–12.
139. Johansson-Lindbom B, Svensson M, Wurbel MA et al., Selective generation of gut tropic T cells in gut-associated lymphoid tissue (GALT): Requirement for GALT dendritic cells and adjuvant, J Exp Med, 2003;198:963–9.
140. Mora JR, Bono MR, Manjunath N, et al., Selective imprinting of gut-homing T cells by Peyer’s patch dendritic cells, Nature, 2003;424:88–93.
141. Dudda JC, Simon JC, Martin S, Dendritic cell immunization route determines CD8+ T cell trafficking to inflamed skin: Role for tissue microenvironment and dendritic cells in establishment of T cell-homing subsets, J Immunol, 2004;172:857–63.
142. Mora JR, Cheng G, Picarella D, et al., Reciprocal and dynamic control of CD8 T cell homing by dendritic cells from skin- and gut-associated lymphoid tissues, J Exp Med, 2005;201:303–16.
143. Ferguson AR, Engelhard VH, CD8 T cells activated in distinct lymphoid organs differentially express adhesion proteins and coexpress multiple chemokine receptors, J Immunol, 2010;184:4079–86.
144. Kershaw MH, Wang G, Westwood, et al., Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2, Hum Gene Ther, 2002;13:1971–80.
145. Idorn M, Thor Straten P, Svane IM, Met O, Transfection of tumorinfiltrating T cells with mRNA encoding CXCR2, Methods Mol Biol, 2016;1428:261–76.
146. Di Stasi A, De Angelis B, Rooney CM, et al., T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model, , 2009;113:6392–402.
147. Craddock JA, Lu A, Bear A, et al., Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b, J Immunother, 2010;33:780–8.
148. Moon EK, Carpenito C, Sun J, et al., Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor, Clin Cancer Res, 2011;17:4719–30.
149. Siddiqui I, Erreni M, van Brakel M, et al., Enhanced recruitment of genetically modified CX3CR1-positive human T cells into Fractalkine/CX3CL1 expressing tumors: Importance of the chemokine gradient, J Immunother Cancer, 2016;4:21.
150. Carlsten M, Levy E, Karambelkar A, et al., Efficient mRNA-based genetic engineering of human NK cells with high-affinity CD16 and CCR7 augments rituximab-induced ADCC against lymphoma and targets NK cell migration toward the lymph node-associated chemokine CCL19, Front Immunol, 2016;7:105.
151. Xu Y, Hyun YM, Lim K, et al., Optogenetic control of chemokine receptor signal and T-cell migration, Proc Natl Acad Sci U S A, 2014;111:6371–6.
152. Soriano JL, Batista N, Santiesteban E, et al., Metronomic cyclophosphamide and methotrexate chemotherapy combined with 1E10 anti-idiotype vaccine in metastatic breast cancer, Int J Breast Cancer, 2011;2011:710292.
153. Hu J, Zhu S, Xia X, et al., CD8+T cell-specific induction of NKG2D receptor by doxorubicin plus interleukin-12 and its contribution to CD8+T cell accumulation in tumors, Mol Cancer, 2014;13:34.
154. Chinnasamy D, Yu Z, Kerkar SP, et al., Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice, Clin Cancer Res, 2012;18:1672–83.
155. Dirkx AE, Oude Egbrink MG, Kuijpers MJ, et al., Tumor angiogenesis modulates leukocyte-vessel wall interactions in vivo by reducing endothelial adhesion molecule expression, Cancer Res, 2003;63:2322–9.
156. Shrimali RK, Yu Z, Theoret MR, et al., Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer, Cancer Res, 2010;70:6171–80.
157. Dirkx AE, Oude Egbrink MG, Castermans K, et al., Antiangiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors, FASEB J, 2006;20:621–30.
158. Ganss R, Ryschich E, Klar E, et al., Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication, Cancer Res, 2002;62:1462–70.
159. Buckanovich RJ, Facciabene A, Kim S, et al., Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy, Nat Med, 2008;14:28–36.
160. Legler DF, Johnson-Leger C, Wiedle G, et al., The alpha v beta 3 integrin as a tumor homing ligand for lymphocytes, Eur J Immunol, 2004;34:1608–16.
161. Wu L, Yun Z, Tagawa T, et al., CTLA-4 blockade expands infiltrating T cells and inhibits cancer cell repopulation during the intervals of chemotherapy in murine mesothelioma, Mol Cancer Ther, 2012;11:1809–19.
162. Kobold S, Steffen J, Chaloupka M, et al., Selective bispecific T cell recruiting antibody and antitumor activity of adoptive T cell transfer, J Natl Cancer Inst, 2015;107:364.
163. Parente-Pereira AC, Burnet J, Ellison D, et al., Trafficking of CAR-engineered human T cells following regional or systemic adoptive transfer in SCID beige mice, J Clin Immunol, 2011;31:710–8.
164. Adusumilli PS, Cherkassky L, Villena-Vargas J, et al., Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity, Sci Transl Med, 2014;6:261ra151.
Keywords: Adoptive T cell therapy, homing, immune supression, antigen recognition, CAR T cells, TCR T cells, TILs, chemokine receptors