Adoptive cellular therapy of cancer: exploring innate and adaptive cellular crosstalk to improve anti-tumor efficacy

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References

• 1 Sengupta N, MacFie TS, MacDonald TT, Pennington D, Silver AR. Cancer immunoediting and “spontaneous” tumor regression. Pathol. Res. Pract. 206(1), 1–8 (2010).
  Medline CASGoogle Scholar
• 2 Gatti RA, Good RA. Occurrence of malignancy in immunodeficiency diseases. A literature review. Cancer 28(1), 89–98 (1971).
  Medline CASGoogle Scholar
• 3 Sheil AG, Mahoney JF, Horvath JS et al. Cancer following renal transplantation. Aust. NZ J. Surg. 49(6), 617–620 (1979).
  Medline CASGoogle Scholar
• 4 Dudley ME, Wunderlich JR, Yang JC et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J. Clin. Oncol. 23(10), 2346–2357 (2005).
  Medline CASGoogle Scholar
• 5 Kalos M, Levine BL, Porter DL et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3(95), 95ra73 (2011).• Describes the potential of chimeric antigen receptor-modified T cells for the effective treatment of B-cell malignancies.
  Medline CASGoogle Scholar
• 6 Grupp SA, Kalos M, Barrett D et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368(16), 1509–1518 (2013).
  Medline CASGoogle Scholar
• 7 Morgan RA, Dudley ME, Wunderlich JR et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314(5796), 126–129 (2006).• Describes the therapeutic potential of genetically engineered cells for the biological therapy of cancer.
  Medline CASGoogle Scholar
• 8 Johnson LA, Morgan RA, Dudley ME et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114(3), 535–546 (2009).
  Medline CASGoogle Scholar
• 9 Park JR, Digiusto DL, Slovak M et al. Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol. Ther. 15(4), 825–833 (2007).
  Medline CASGoogle Scholar
• 10 Riddell SR, Jensen MC, June CH. Chimeric antigen receptor-modified T cells: clinical translation in stem cell transplantation and beyond. Biol. Blood Marrow Transplant. 19(1 Suppl), S2–S5 (2013).
  Medline CASGoogle Scholar
• 11 Kershaw MH, Westwood JA, Parker LL et al. A Phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin. Cancer Res. 12(20 Pt 1), 6106–6115 (2006).
  Medline CASGoogle Scholar
• 12 Lamers CH, Sleijfer S, Vulto AG et al. Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J. Clin. Oncol. 24(13), e20–e22 (2006).
  MedlineGoogle Scholar
• 13 Brahmer JR, Tykodi SS, Chow LQ et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366(26), 2455–2465 (2012).
  Medline CASGoogle Scholar
• 14 Maker AV, Phan GQ, Attia P et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a Phase I/II study. Ann. Surg. Oncol. 12(12), 1005–1016 (2005).
  MedlineGoogle Scholar
• 15 Topalian SL, Hodi FS, Brahmer JR et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366(26), 2443–2454 (2012).
  Medline CASGoogle Scholar
• 16 Hamid O, Robert C, Daud A et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369(2), 134–144 (2013).
  Medline CASGoogle Scholar
• 17 Laurent S, Queirolo P, Boero S et al. The engagement of CTLA-4 on primary melanoma cell lines induces antibody-dependent cellular cytotoxicity and TNF-alpha production. J. Transl. Med. 11, 108 (2013).
  Medline CASGoogle Scholar
• 18 Benson DM Jr, Bakan CE, Mishra A et al. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood 116(13), 2286–2294 (2010).
  Medline CASGoogle Scholar
• 19 Wang XF, Lei Y, Chen M, Chen CB, Ren H, Shi TD. PD-1/PDL1 and CD28/CD80 pathways modulate natural killer T cell function to inhibit hepatitis B virus replication. J. Viral Hepat. 20(Suppl. 1), 27–39 (2013).
  Medline CASGoogle Scholar
• 20 Lanier LL, Sun JC. Do the terms innate and adaptive immunity create conceptual barriers? Nat. Rev. Immunol. 9(5), 302–303 (2009).
  Medline CASGoogle Scholar
• 21 Shanker A, Marincola FM. Cooperativity of adaptive and innate immunity: implications for cancer therapy. Cancer Immunol. Immunother. 60(8), 1061–1074 (2011).
  Medline CASGoogle Scholar
• 22 Hegde S, Chen X, Keaton JM, Reddington F, Besra GS, Gumperz JE. NKT cells direct monocytes into a DC differentiation pathway. J. Leukoc. Biol. 81(5), 1224–1235 (2007).
  Medline CASGoogle Scholar
• 23 Mocikat R, Braumuller H, Gumy A et al. Natural killer cells activated by MHC class I(low) targets prime dendritic cells to induce protective CD8 T cell responses. Immunity 19(4), 561–569 (2003).
  Medline CASGoogle Scholar
• 24 Ko HJ, Lee JM, Kim YJ, Kim YS, Lee KA, Kang CY. Immunosuppressive myeloid-derived suppressor cells can be converted into immunogenic APCs with the help of activated NKT cells: an alternative cell-based antitumor vaccine. J. Immunol. 182(4), 1818–1828 (2009).•• Describes the ability of activated natural killer T cells to convert myeloid-derived suppressor cells into immunogenic dendritic cells.
  Medline CASGoogle Scholar
• 25 Lee JM, Seo JH, Kim YJ, Kim YS, Ko HJ, Kang CY. The restoration of myeloid-derived suppressor cells as functional antigen-presenting cells by NKT cell help and all-trans-retinoic acid treatment. Int. J. Cancer 131(3), 741–751 (2012).
  Medline CASGoogle Scholar
• 26 Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 233(4770), 1318–1321 (1986).
  Medline CASGoogle Scholar
• 27 Rosenberg SA, Packard BS, Aebersold PM et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N. Engl. J. Med. 319(25), 1676–1680 (1988).•• First-in-human study using tumor-infiltrating lymphocytes expanded in IL-2 to treat patients with metastatic melanoma.
  Medline CASGoogle Scholar
• 28 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. 17(13), 4550–4557 (2011).
  Medline CASGoogle Scholar
• 29 Holmes EC. Immunology of tumor infiltrating lymphocytes. Ann. Surg. 201(2), 158–163 (1985).
  Medline CASGoogle Scholar
• 30 Kowalczyk D, Skorupski W, Kwias Z, Nowak J. Flow cytometric analysis of tumour-infiltrating lymphocytes in patients with renal cell carcinoma. Br. J. Urol. 80(4), 543–547 (1997).
  Medline CASGoogle Scholar
• 31 Junker N, Thor Straten P, Andersen MH, Svane IM. Characterization of ex vivo expanded tumor infiltrating lymphocytes from patients with malignant melanoma for clinical application. J. Skin Cancer. 2011, 574695 (2011).
  MedlineGoogle Scholar
• 32 Dudley ME, Gross CA, Somerville RP et al. Randomized selection design trial evaluating CD8⁺-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma. J. Clin. Oncol. 31(17), 2152–2159 (2013).
  Medline CASGoogle Scholar
• 33 Takahashi T, Chiba S, Nieda M et al. Cutting edge: analysis of human V alpha 24⁺CD8⁺ NK T cells activated by alpha-galactosylceramide-pulsed monocyte-derived dendritic cells. J. Immunol. 168(7), 3140–3144 (2002).
  Medline CASGoogle Scholar
• 34 Bendelac A, Killeen N, Littman DR, Schwartz RH. A subset of CD4⁺ thymocytes selected by MHC class I molecules. Science 263(5154), 1774–1778 (1994).
  Medline CASGoogle Scholar
• 35 Campbell JP, Guy K, Cosgrove C, Florida-James GD, Simpson RJ. Total lymphocyte CD8 expression is not a reliable marker of cytotoxic T-cell populations in human peripheral blood following an acute bout of high-intensity exercise. Brain Behav. Immun. 22(3), 375–380 (2008).
  Medline CASGoogle Scholar
• 36 Gannon GA, Rhind SG, Shek PN, Shephard RJ. Differential cell adhesion molecule expression and lymphocyte mobilisation during prolonged aerobic exercise. Eur. J. Appl. Physiol. 84(4), 272–282 (2001).
  Medline CASGoogle Scholar
• 37 Simpson RJ, Florida-James GD, Cosgrove C et al. High-intensity exercise elicits the mobilization of senescent T lymphocytes into the peripheral blood compartment in human subjects. J. Appl. Physiol. (1985) 103(1), 396–401 (2007).
  Medline CASGoogle Scholar
• 38 Goff SL, Smith FO, Klapper JA et al. Tumor infiltrating lymphocyte therapy for metastatic melanoma: analysis of tumors resected for TIL. J. Immunother. 33(8), 840–847 (2010).
  MedlineGoogle Scholar
• 39 Yannelli JR, Hyatt C, McConnell S et al. Growth of tumor-infiltrating lymphocytes from human solid cancers: summary of a 5-year experience. Int. J. Cancer 65(4), 413–421 (1996).
  Medline CASGoogle Scholar
• 40 Fabbri M, Ridolfi R, Maltoni R et al. Tumor infiltrating lymphocytes and continuous infusion interleukin-2 after metastasectomy in 61 patients with melanoma, colorectal and renal carcinoma. Tumori 86(1), 46–52 (2000).
  Medline CASGoogle Scholar
• 41 Ridolfi R, Flamini E, Riccobon A et al. Adjuvant adoptive immunotherapy with tumour-infiltrating lymphocytes and modulated doses of interleukin-2 in 22 patients with melanoma, colorectal and renal cancer, after radical metastasectomy, and in 12 advanced patients. Cancer Immunol. Immunother. 46(4), 185–193 (1998).
  Medline CASGoogle Scholar
• 42 Sadelain M, Riviere I, Brentjens R. Targeting tumours with genetically enhanced T lymphocytes. Nat. Rev. Cancer. 3(1), 35–45 (2003).
  Medline CASGoogle Scholar
• 43 Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc. Natl Acad. Sci. USA 86(24), 10024–10028 (1989).
  Medline CASGoogle Scholar
• 44 Rosenberg SA. Cell transfer immunotherapy for metastatic solid cancer – what clinicians need to know. Nat. Rev. Clin. Oncol. 8(10), 577–585 (2011).
  Medline CASGoogle Scholar
• 45 Gilham DE, Debets R, Pule M, Hawkins RE, Abken H. CAR-T cells and solid tumors: tuning T cells to challenge an inveterate foe. Trends Mol. Med. 18(7), 377–384 (2012).
  Medline CASGoogle Scholar
• 46 Mardiros A, Dos Santos C, McDonald T et al. T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia. Blood 122(18), 3138–3148 (2013).
  Medline CASGoogle Scholar
• 47 Pizzitola I, Anjos-Afonso F, Rouault-Pierre K et al. Chimeric antigen receptors against CD33/CD123 antigens efficiently target primary acute myeloid leukemia cells in vivo. Leukemia doi:10.1038/leu.2014.62 (2014) (Epub ahead of print).
  MedlineGoogle Scholar
• 48 Jordan CT, Upchurch D, Szilvassy SJ et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia 14(10), 1777–1784 (2000).
  Medline CASGoogle Scholar
• 49 Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365(8), 725–733 (2011).
  Medline CASGoogle Scholar
• 50 Kochenderfer JN, Dudley ME, Feldman SA et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 119(12), 2709–2720 (2012).
  Medline CASGoogle Scholar
• 51 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 116(20), 4099–4102 (2010).
  Medline CASGoogle Scholar
• 52 Chustecka Zosia. Excitement over CAR-engineered T-cells in leukemia and lymphoma. Medscape (2013). www.medscape.com/viewarticle/817453 
  Google Scholar
• 53 Hoelzer D. Targeted therapy with monoclonal antibodies in acute lymphoblastic leukemia. Curr. Opin. Oncol. 25(6), 701–706 (2013).
  Medline CASGoogle Scholar
• 54 Huang PY, Best OG, Almazi JG et al. Cell surface phenotype profiles distinguish stable and progressive chronic lymphocytic leukemia. Leuk. Lymphoma 55(9), 2085–2092 (2014).
  Medline CASGoogle Scholar
• 55 Till BG, Jensen MC, Wang J et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 112(6), 2261–2271 (2008).
  Medline CASGoogle Scholar
• 56 Kowolik CM, Topp MS, Gonzalez S et al. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res. 66(22), 10995–11004 (2006).
  Medline CASGoogle Scholar
• 57 Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol. Ther. 18(4), 843–851 (2010).
  Medline CASGoogle Scholar
• 58 Di Stasi A, Tey SK, Dotti G et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365(18), 1673–1683 (2011).
  Medline CASGoogle Scholar
• 59 Kofler DM, Chmielewski M, Rappl G et al. CD28 costimulation Impairs the efficacy of a redirected T-cell antitumor attack in the presence of regulatory T cells which can be overcome by preventing Lck activation. Mol. Ther. 19(4), 760–767 (2011).
  Medline CASGoogle Scholar
• 60 Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol. Immunother. 58(1), 49–59 (2009).
  Medline CASGoogle Scholar
• 61 Dembic Z, Haas W, Weiss S et al. Transfer of specificity by murine alpha and beta T-cell receptor genes. Nature 320(6059), 232–238 (1986).
  Medline CASGoogle Scholar
• 62 Clay TM, Custer MC, Sachs J, Hwu P, Rosenberg SA, Nishimura MI. Efficient transfer of a tumor antigen-reactive TCR to human peripheral blood lymphocytes confers anti-tumor reactivity. J. Immunol. 163(1), 507–513 (1999).
  Medline CASGoogle Scholar
• 63 Bunnell BA, Muul LM, Donahue RE, Blaese RM, Morgan RA. High-efficiency retroviral-mediated gene transfer into human and nonhuman primate peripheral blood lymphocytes. Proc. Natl Acad. Sci. USA 92(17), 7739–7743 (1995).
  Medline CASGoogle Scholar
• 64 Mavilio F, Ferrari G, Rossini S et al. Peripheral blood lymphocytes as target cells of retroviral vector-mediated gene transfer. Blood 83(7), 1988–1997 (1994).
  Medline CASGoogle Scholar
• 65 Riviere I, Gallardo HF, Hagani AB, Sadelain M. Retroviral-mediated gene transfer in primary murine and human T-lymphocytes. Mol. Biotechnol. 15(2), 133–142 (2000).
  Medline CASGoogle Scholar
• 66 Bobisse S, Rondina M, Merlo A et al. Reprogramming T lymphocytes for melanoma adoptive immunotherapy by T-cell receptor gene transfer with lentiviral vectors. Cancer Res. 69(24), 9385–9394 (2009).
  Medline CASGoogle Scholar
• 67 Circosta P, Granziero L, Follenzi A et al. T cell receptor (TCR) gene transfer with lentiviral vectors allows efficient redirection of tumor specificity in naive and memory T cells without prior stimulation of endogenous TCR. Hum. Gene Ther. 20(12), 1576–1588 (2009).
  Medline CASGoogle Scholar
• 68 Field AC, Vink C, Gabriel R et al. Comparison of lentiviral and Sleeping Beauty mediated alphabeta T cell receptor gene transfer. PLoS ONE 8(6), e68201 (2013).
  Medline CASGoogle Scholar
• 69 Uttenthal BJ, Chua I, Morris EC, Stauss HJ. Challenges in T cell receptor gene therapy. J. Gene Med. 14(6), 386–399 (2012).
  Medline CASGoogle Scholar
• 70 Ahmadi M, King JW, Xue SA et al. CD3 limits the efficacy of TCR gene therapy in vivo. Blood 118(13), 3528–3537 (2011).
  Medline CASGoogle Scholar
• 71 Okamoto S, Mineno J, Ikeda H et al. Improved expression and reactivity of transduced tumor-specific TCRs in human lymphocytes by specific silencing of endogenous TCR. Cancer Res. 69(23), 9003–9011 (2009).
  Medline CASGoogle Scholar
• 72 Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer. Cell. 21(3), 309–322 (2012).
  Medline CASGoogle Scholar
• 73 Morales JK, Kmieciak M, Knutson KL, Bear HD, Manjili MH. GM-CSF is one of the main breast tumor-derived soluble factors involved in the differentiation of CD11b-Gr1- bone marrow progenitor cells into myeloid-derived suppressor cells. Breast Cancer Res. Treat. 123(1), 39–49 (2010).
  Medline CASGoogle Scholar
• 74 Ostrand-Rosenberg S. Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol. Immunother. 59(10), 1593–1600 (2010).
  MedlineGoogle Scholar
• 75 Pastula A, Marcinkiewicz J. Myeloid-derived suppressor cells: a double-edged sword? Int. J. Exp. Pathol. 92(2), 73–78 (2011).
  Medline CASGoogle Scholar
• 76 Morales JK, Kmieciak M, Graham L, Feldmesser M, Bear HD, Manjili MH. Adoptive transfer of HER2/neu-specific T cells expanded with alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid-derived suppressor cells. Cancer Immunol. Immunother. 58(6), 941–953 (2009).
  Medline CASGoogle Scholar
• 77 Dugast AS, Haudebourg T, Coulon F et al. Myeloid-derived suppressor cells accumulate in kidney allograft tolerance and specifically suppress effector T cell expansion. J. Immunol. 180(12), 7898–7906 (2008).
  Medline CASGoogle Scholar
• 78 Serafini P, Mgebroff S, Noonan K, Borrello I. Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res. 68(13), 5439–5449 (2008).
  Medline CASGoogle Scholar
• 79 Luan Y, Mosheir E, Menon MC et al. Monocytic myeloid-derived suppressor cells accumulate in renal transplant patients and mediate CD4⁺ Foxp3⁺ Treg expansion. Am. J. Transplant. 13(12), 3123–3131 (2013).
  Medline CASGoogle Scholar
• 80 Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12(4), 253–268 (2012).
  Medline CASGoogle Scholar
• 81 Kmieciak M, Basu D, Payne KK et al. Activated NKT cells and NK cells render T cells resistant to myeloid-derived suppressor cells and result in an effective adoptive cellular therapy against breast cancer in the FVBN202 transgenic mouse. J. Immunol. 187(2), 708–717 (2011).
  Medline CASGoogle Scholar
• 82 Payne KK, Zoon CK, Wan W et al. Peripheral blood mononuclear cells of patients with breast cancer can be reprogrammed to enhance anti-HER-2/neu reactivity and overcome myeloid-derived suppressor cells. Breast Cancer Res. Treat. 142(1), 45–57 (2013).• First-in-human study to demonstrate reprogrammed immune cells contain activated natural killer T cells that can overcome myeloid-derived suppressor cell-mediated suppression
  Medline CASGoogle Scholar
• 83 Moreno M, Molling JW, von Mensdorff-Pouilly S et al. IFN-gamma-producing human invariant NKT cells promote tumor-associated antigen-specific cytotoxic T cell responses. J. Immunol. 181(4), 2446–2454 (2008).
  Medline CASGoogle Scholar
• 84 Stober D, Jomantaite I, Schirmbeck R, Reimann J. NKT cells provide help for dendritic cell-dependent priming of MHC class I-restricted CD8⁺ T cells in vivo. J. Immunol. 170(5), 2540–2548 (2003).
  Medline CASGoogle Scholar
• 85 Hermans IF, Silk JD, Gileadi U et al. NKT cells enhance CD4⁺ and CD8⁺ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells. J. Immunol. 171(10), 5140–5147 (2003).
  Medline CASGoogle Scholar
• 86 Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G. Reciprocal activating interaction between natural killer cells and dendritic cells. J. Exp. Med. 195(3), 327–333 (2002).• Demonstrates for the first time bidirectional crosstalk between natural killer cells and dendritic cells, leading to natural killer cell induction of dendritic cell maturation.
  Medline CASGoogle Scholar
• 87 Goldszmid RS, Caspar P, Rivollier A et al. NK cell-derived interferon-gamma orchestrates cellular dynamics and the differentiation of monocytes into dendritic cells at the site of infection. Immunity 36(6), 1047–1059 (2012).
  Medline CASGoogle Scholar
• 88 Zhang AL, Colmenero P, Purath U et al. Natural killer cells trigger differentiation of monocytes into dendritic cells. Blood 110(7), 2484–2493 (2007).
  Medline CASGoogle Scholar
• 89 Kalinski P, Mailliard RB, Giermasz A et al. Natural killer-dendritic cell cross-talk in cancer immunotherapy. Expert Opin. Biol. Ther. 5(10), 1303–1315 (2005).
  Medline CASGoogle Scholar
• 90 Wong JL, Berk E, Edwards RP, Kalinski P. IL-18-primed helper NK cells collaborate with dendritic cells to promote recruitment of effector CD8+ T cells to the tumor microenvironment. Cancer Res. (2013).
  Google Scholar
• 91 Srivastava RM, Lee SC, Andrade Filho PA et al. Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients. Clin. Cancer Res. 19(7), 1858–1872 (2013).
  Medline CASGoogle Scholar
• 92 Herr W, Wolfel T, Heike M, Meyer zum Buschenfelde KH, Knuth A. Frequency analysis of tumor-reactive cytotoxic T lymphocytes in peripheral blood of a melanoma patient vaccinated with autologous tumor cells. Cancer Immunol. Immunother. 39(2), 93–99 (1994).
  Medline CASGoogle Scholar
• 93 Germeau C, Ma W, Schiavetti F et al. High frequency of antitumor T cells in the blood of melanoma patients before and after vaccination with tumor antigens. J. Exp. Med. 201(2), 241–248 (2005).
  Medline CASGoogle Scholar
• 94 Jager E, Jager D, Karbach J et al. Identification of NY-ESO-1 epitopes presented by human histocompatibility antigen (HLA)-DRB4*0101-0103 and recognized by CD4⁺ T lymphocytes of patients with NY-ESO-1-expressing melanoma. J. Exp. Med. 191(4), 625–630 (2000).
  Medline CASGoogle Scholar
• 95 Kmieciak M, Payne KK, Idowu MO et al. Tumor escape and progression of HER-2/neu negative breast cancer under immune pressure. J. Transl. Med. 9, 35 (2011).
  Medline CASGoogle Scholar
• 96 Marits P, Karlsson M, Sherif A, Garske U, Thorn M, Winqvist O. Detection of immune responses against urinary bladder cancer in sentinel lymph nodes. J. Nucl. Med. 49(1), 59–70 (2006).
  Google Scholar
• 97 Marits P, Karlsson M, Dahl K et al. Sentinel node lymphocytes: tumour reactive lymphocytes identified intraoperatively for the use in immunotherapy of colon cancer. Br. J. Cancer 94(10), 1478–1484 (2006).
  Medline CASGoogle Scholar
• 98 Trickett A, Kwan YL. T cell stimulation and expansion using anti-CD3/CD28 beads. J. Immunol. Meth. 275(1–2), 251–255 (2003).
  Medline CASGoogle Scholar
• 99 Riddell SR, Greenberg PD. The use of anti-CD3 and anti-CD28 monoclonal antibodies to clone and expand human antigen-specific T cells. J. Immunol. Meth. 128(2), 189–201 (1990).
  Medline CASGoogle Scholar
• 100 Fleming MD, Bear HD, Lipshy K et al. Adoptive transfer of bryostatin-activated tumor-sensitized lymphocytes prevents or destroys tumor metastases without expansion in vitro. J. Immunother. Emphasis. Tumor. Immunol. 18(3), 147–155 (1995).
  Medline CASGoogle Scholar
• 101 Esa AH, Boto WO, Adler WH, May WS, Hess AD. Activation of T-cells by bryostatins: induction of the IL-2 receptor gene transcription and down-modulation of surface receptors. Int. J. Immunopharmacol. 12(5), 481–490 (1990).
  Medline CASGoogle Scholar
• 102 Hess AD, Silanskis MK, Esa AH, Pettit GR, May WS. Activation of human T lymphocytes by bryostatin. J. Immunol. 141(10), 3263–3269 (1988).
  Medline CASGoogle Scholar
• 103 von Essen MR, Kongsbak M, Levring TB et al. PKC-theta exists in an oxidized inactive form in naive human T cells. Eur. J. Immunol. 43(6), 1659–1666 (2013).
  MedlineGoogle Scholar
• 104 von Essen M, Nielsen MW, Bonefeld CM et al. Protein kinase C (PKC) alpha and PKC theta are the major PKC isotypes involved in TCR down-regulation. J. Immunol. 176(12), 7502–7510 (2006).
  Medline CASGoogle Scholar
• 105 Monks CR, Freiberg BA, Kupfer H, Sciaky N, Kupfer A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395(6697), 82–86 (1998).
  Medline CASGoogle Scholar
• 106 Sims TN, Soos TJ, Xenias HS et al. Opposing effects of PKCtheta and WASp on symmetry breaking and relocation of the immunological synapse. Cell 129(4), 773–785 (2007).
  Medline CASGoogle Scholar
• 107 Anel A, Aguilo JI, Catalan E et al. Protein kinase C-theta (PKC-theta) in natural killer cell function and anti-tumor immunity. Front. Immunol. 3, 187 (2012).
  Medline CASGoogle Scholar
• 108 Grant S, Roberts J, Poplin E et al. Phase Ib trial of bryostatin 1 in patients with refractory malignancies. Clin. Cancer Res. 4(3), 611–618 (1998).
  Medline CASGoogle Scholar
• 109 Klebanoff CA, Gattinoni L, Torabi–Parizi P et al. Central memory self/tumor-reactive CD8⁺ T cells confer superior antitumor immunity compared with effector memory T cells. Proc. Natl Acad. Sci. USA 102(27), 9571–9576 (2005).• Describes the efficacy of central memory T cells against tumor compared with other T cell subsets.
  Medline CASGoogle Scholar
• 110 Perret R, Ronchese F. Memory T cells in cancer immunotherapy: which CD8 T-cell population provides the best protection against tumours? Tissue Antigens 72(3), 187–194 (2008).
  Medline CASGoogle Scholar
• 111 Cha E, Graham L, Manjili MH, Bear HD. IL-7 + IL-15 are superior to IL-2 for the ex vivo expansion of 4T1 mammary carcinoma-specific T cells with greater efficacy against tumors in vivo. Breast Cancer Res. Treat. 122(2), 359–369 (2010).
  Medline CASGoogle Scholar
• 112 Le HK, Graham L, Miller CH, Kmieciak M, Manjili MH, Bear HD. Incubation of antigen-sensitized T lymphocytes activated with bryostatin 1 + ionomycin in IL-7 + IL-15 increases yield of cells capable of inducing regression of melanoma metastases compared with culture in IL-2. Cancer Immunol. Immunother. 58(10), 1565–1576 (2009).
  Medline CASGoogle Scholar
• 113 Tan JT, Dudl E, LeRoy E et al. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc. Natl Acad. Sci. USA 98(15), 8732–8737 (2001).
  Medline CASGoogle Scholar
• 114 Tan JT, Ernst B, Kieper WC, LeRoy E, Sprent J, Surh CD. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8⁺ cells but are not required for memory phenotype CD4⁺ cells. J. Exp. Med. 195(12), 1523–1532 (2002).
  Medline CASGoogle Scholar
• 115 Gordy LE, Bezbradica JS, Flyak AI et al. IL-15 regulates homeostasis and terminal maturation of NKT cells. J. Immunol. 187(12), 6335–6345 (2011).
  Medline CASGoogle Scholar
• 116 Schluns KS, Lefrancois L. Cytokine control of memory T-cell development and survival. Nat. Rev. Immunol. 3(4), 269–279 (2003).
  Medline CASGoogle Scholar
• 117 Pillet AH, Bugault F, Theze J, Chakrabarti LA, Rose T. A programmed switch from IL-15- to IL-2-dependent activation in human NK cells. J. Immunol. 182(10), 6267–6277 (2009).
  Medline CASGoogle Scholar
• 118 Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38(1), 13–25 (2013).
  Medline CASGoogle Scholar
• 119 Leonard WJ, Kronke M, Peffer NJ, Depper JM, Greene WC. Interleukin 2 receptor gene expression in normal human T lymphocytes. Proc. Natl Acad. Sci. USA 82(18), 6281–6285 (1985).
  Medline CASGoogle Scholar
• 120 Williams MA, Tyznik AJ, Bevan MJ. Interleukin-2 signals during priming are required for secondary expansion of CD8⁺ memory T cells. Nature 441(7095), 890–893 (2006).
  Medline CASGoogle Scholar
• 121 Dai Z, Konieczny BT, Lakkis FG. The dual role of IL-2 in the generation and maintenance of CD8⁺ memory T cells. J. Immunol. 165(6), 3031–3036 (2000).
  Medline CASGoogle Scholar
• 122 Caligiuri MA, Murray C, Robertson MJ et al. Selective modulation of human natural killer cells in vivo after prolonged infusion of low dose recombinant interleukin 2. J. Clin. Invest. 91(1), 123–132 (1993).
  Medline CASGoogle Scholar
• 123 Henney CS, Kuribayashi K, Kern DE, Gillis S. Interleukin-2 augments natural killer cell activity. Nature 291(5813), 335–338 (1981).
  Medline CASGoogle Scholar
• 124 Horowitz A, Newman KC, Evans JH, Korbel DS, Davis DM, Riley EM. Cross-talk between T cells and NK cells generates rapid effector responses to Plasmodium falciparum-infected erythrocytes. J. Immunol. 184(11), 6043–6052 (2010).
  Medline CASGoogle Scholar
• 125 Gasteiger G, Hemmers S, Bos PD, Sun JC, Rudensky AY. IL-2-dependent adaptive control of NK cell homeostasis. J. Exp. Med. 210(6), 1179–1187 (2013).
  Medline CASGoogle Scholar
• 126 Gasteiger G, Hemmers S, Firth MA et al. IL-2-dependent tuning of NK cell sensitivity for target cells is controlled by regulatory T cells. J. Exp. Med. 210(6), 1167–1178 (2013).
  Medline CASGoogle Scholar
• 127 Sitrin J, Ring A, Garcia KC, Benoist C, Mathis D. Regulatory T cells control NK cells in an insulitic lesion by depriving them of IL-2. J. Exp. Med. 210(6), 1153–1165 (2013).
  Medline CASGoogle Scholar
• 128 Bessoles S, Fouret F, Dudal S, Besra GS, Sanchez F, Lafont V. IL-2 triggers specific signaling pathways in human NKT cells leading to the production of pro- and anti-inflammatory cytokines. J. Leukoc. Biol. 84(1), 224–233 (2008).
  Medline CASGoogle Scholar
• 129 Chen Q, Kim YC, Laurence A, Punkosdy GA, Shevach EM. IL-2 controls the stability of Foxp3 expression in TGF-beta-induced Foxp3⁺ T cells in vivo. J. Immunol. 186(11), 6329–6337 (2011).
  Medline CASGoogle Scholar
• 130 Guo Z, Khattar M, Schroder PM et al. A dynamic dual role of IL-2 signaling in the two–step differentiation process of adaptive regulatory T cells. J. Immunol. 190(7), 3153–3162 (2013).
  Medline CASGoogle Scholar
• 131 Cheng G, Yuan X, Tsai MS, Podack ER, Yu A, Malek TR. IL-2 receptor signaling is essential for the development of Klrg1⁺ terminally differentiated T regulatory cells. J. Immunol. 189(4), 1780–1791 (2012).
  Medline CASGoogle Scholar
• 132 Kmieciak M, Gowda M, Graham L et al. Human T cells express CD25 and Foxp3 upon activation and exhibit effector/memory phenotypes without any regulatory/suppressor function. J. Transl. Med. 7, 89 (2009).
  MedlineGoogle Scholar
• 133 Malek TR, Castro I. Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity 33(2), 153–165 (2010).
  Medline CASGoogle Scholar
• 134 Boyman O, Kovar M, Rubinstein MP, Surh CD, Sprent J. Selective stimulation of T cell subsets with antibody–cytokine immune complexes. Science 311(5769), 1924–1927 (2006).
  Medline CASGoogle Scholar
• 135 Refaeli Y, Van Parijs L, London CA, Tschopp J, Abbas AK. Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. Immunity 8(5), 615–623 (1998).
  Medline CASGoogle Scholar
• 136 Lenardo MJ. Fas and the art of lymphocyte maintenance. J. Exp. Med. 183(3), 721–724 (1996).
  Medline CASGoogle Scholar
• 137 Kaech SM, Tan JT, Wherry EJ, Konieczny BT, Surh CD, Ahmed R. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long–lived memory cells. Nat. Immunol. 4(12), 1191–1198 (2003).
  Medline CASGoogle Scholar
• 138 Li J, Huston G, Swain SL. IL-7 promotes the transition of CD4 effectors to persistent memory cells. J. Exp. Med. 198(12), 1807–1815 (2003).
  Medline CASGoogle Scholar
• 139 Michaud A, Dardari R, Charrier E, Cordeiro P, Herblot S, Duval M. IL-7 enhances survival of human CD56bright NK cells. J. Immunother. 33(4), 382–390 (2010).
  Medline CASGoogle Scholar
• 140 Vosshenrich CA, Ranson T, Samson SI et al. Roles for common cytokine receptor gamma-chain-dependent cytokines in the generation, differentiation, and maturation of NK cell precursors and peripheral NK cells in vivo. J. Immunol. 174(3), 1213–1221 (2005).
  Medline CASGoogle Scholar
• 141 de Lalla C, Festuccia N, Albrecht I et al. Innate-like effector differentiation of human invariant NKT cells driven by IL-7. J. Immunol. 180(7), 4415–4424 (2008).
  Medline CASGoogle Scholar
• 142 Giri JG, Anderson DM, Kumaki S, Park LS, Grabstein KH, Cosman D. IL-15, a novel T cell growth factor that shares activities and receptor components with IL-2. J. Leukoc. Biol. 57(5), 763–766 (1995).
  Medline CASGoogle Scholar
• 143 Dubois S, Mariner J, Waldmann TA, Tagaya Y. IL-15Ralpha recycles and presents IL-15 in trans to neighboring cells. Immunity 17(5), 537–547 (2002).
  Medline CASGoogle Scholar
• 144 Rubinstein MP, Kovar M, Purton JF et al. Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}. Proc. Natl Acad. Sci. USA 103(24), 9166–9171 (2006).
  Medline CASGoogle Scholar
• 145 Mitchell DM, Ravkov EV, Williams MA. Distinct roles for IL-2 and IL-15 in the differentiation and survival of CD8⁺ effector and memory T cells. J. Immunol. 184(12), 6719–6730 (2010).
  Medline CASGoogle Scholar
• 146 Zhang X, Sun S, Hwang I, Tough DF, Sprent J. Potent and selective stimulation of memory-phenotype CD8⁺ T cells in vivo by IL-15. Immunity 8(5), 591–599 (1998).
  Medline CASGoogle Scholar
• 147 Kennedy MK, Glaccum M, Brown SN et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J. Exp. Med. 191(5), 771–780 (2000).
  Medline CASGoogle Scholar
• 148 Lodolce JP, Boone DL, Chai S et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9(5), 669–676 (1998).
  Medline CASGoogle Scholar
• 149 Huntington ND, Legrand N, Alves NL et al. IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. J. Exp. Med. 206(1), 25–34 (2009).
  Medline CASGoogle Scholar
• 150 Lee GA, Liou YH, Wang SW, Ko KL, Jiang ST, Liao NS. Different NK cell developmental events require different levels of IL-15 trans-presentation. J. Immunol. 187(3), 1212–1221 (2011).
  Medline CASGoogle Scholar
• 151 Castillo EF, Acero LF, Stonier SW, Zhou D, Schluns KS. Thymic and peripheral microenvironments differentially mediate development and maturation of iNKT cells by IL-15 transpresentation. Blood 116(14), 2494–2503 (2010).
  Medline CASGoogle Scholar
• 152 Ascierto ML, Idowu MO, Zhao Y et al. Molecular signatures mostly associated with NK cells are predictive of relapse free survival in breast cancer patients. J. Transl. Med. 11(1), 145 (2013).
  Medline CASGoogle Scholar
• 153 Ascierto ML, Kmieciak M, Idowu MO et al. A signature of immune function genes associated with recurrence-free survival in breast cancer patients. Breast Cancer Res. Treat. 131(3), 871–880 (2012).
  Medline CASGoogle Scholar
• 154 Wang Y, Zheng X, Wei H, Sun R, Tian Z. Different roles of IL-15 from IL-2 in differentiation and activation of human CD3⁺CD56⁺ NKT-like cells from cord blood in long term culture. Int. Immunopharmacol. 8(6), 927–934 (2008).
  Medline CASGoogle Scholar
• 155 Gajewski TF, Woo SR, Zha Y et al. Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr. Opin. Immunol. 25(2), 268–276 (2013).
  Medline CASGoogle Scholar
• 156 Gajewski TF, Louahed J, Brichard VG. Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J. 16(4), 399–403 (2010).
  Medline CASGoogle Scholar
• 157 Galon J, Pages F, Marincola FM et al. The immune score as a new possible approach for the classification of cancer. J. Transl. Med. 10, 1 (2012).
  MedlineGoogle Scholar