Skip to main content
SpringerLink
Log in

The Tumor Microenvironment

Regulation of Antitumor Immunity and Implications for Immunotherapy

  • Chapter
Immunotherapy of Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

  • 1160 Accesses

Abstract

After more than 30 yr of crusading against cancer, targeting mostly the tumor cell cycle, the need for novel therapeutic strategies has become increasingly clear. Survival and expansion of tumor cells cannot be achieved in the absence of a favorable microenvironment, the main components of which are leukocytes, vascular cells, and fibroblasts. This tumor microenvironment critically provides growth factors and survival signals for tumor cell proliferation, secretes angiogenic factors that control tumor vascularization, and directs invasion and metastasis through adhesion molecule interactions. In addition, a successful antitumor immune response is prevented by multiple mechanisms of evasion orchestrated by nontumorcells. Understanding how the tumor microenvironment modulates the immune response is vital to designing new potential ways of boosting anticancer immunity. This chapter is focused on providing a rationale for new prospects of manipulating the tumor microenvironment to minimize escape from natural anticancer immune response and targeted immunotherapies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Rosenberg SA. The identification of cancer antigens: impact on the development of cancer vaccines. Cancer J 2000; 6(Suppl 2):S142–149.

    PubMed  Google Scholar 

  2. Zeng G. MHC class II-restricted tumor antigens recognized by CD4+ T cells: new strategies for cancer vaccine design. J Immunother 2001: 24:195–204.

    Article  CAS  Google Scholar 

  3. Novellino L, Castelli C, Parmiani G. A listing of human tumor antigens recognized by T cells: March 2004 update. Cancer Immunol Immunother 2004: 54:187–207.

    Article  PubMed  CAS  Google Scholar 

  4. Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003, 348:203–213.

    Article  PubMed  CAS  Google Scholar 

  5. Schumacher K, Haensch W, Roefzaad C, Schlag PM. Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas. Cancer Res 2001; 61:3932–3936.

    PubMed  CAS  Google Scholar 

  6. Marrogi AJ, Munshi A, Merogi AJ, et al. Study of tumor infiltrating lymphocytes and transforming growth factor-beta as prognostic factors in breast carcinoma. Int J Cancer 1997; 74:492–501.

    Article  PubMed  CAS  Google Scholar 

  7. Vesalainen S, Lipponen P, Talja M, Syrjanen K. Histological grade, perineural infiltration, tumour-infiltrating lymphocytes and apoptosis as determinants of long-term prognosis in prostatic adenocarcinoma. Eur J Cancer 1994; 30A:1797–1803.

    Article  PubMed  CAS  Google Scholar 

  8. Halpern AC, Schuchter LM Prognostic models in melanoma. Semin Oncol 1997; 24:S2–S7.

    PubMed  CAS  Google Scholar 

  9. Naito Y, Saito K, Shiiba K, et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 1998; 58:3491–3494.

    PubMed  CAS  Google Scholar 

  10. Nakano O, Sato M, Naito Y, et al. Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res 2001; 61:5132–5136.

    PubMed  CAS  Google Scholar 

  11. Conejo-Garcia JR, Benencia F, Courreges MC, et al. Ovarian carcinoma expresses the NKG2D ligand Letal and promotes the survival and expansion of CD28(-) antitumor T cells. Cancer Res 2004; 64:2175–2182.

    Article  PubMed  CAS  Google Scholar 

  12. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 2004; 22:329–360.

    Article  PubMed  CAS  Google Scholar 

  13. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 2002; 99:12,293–12,297.

    Article  PubMed  CAS  Google Scholar 

  14. Streubel B, Chott A, Huber D, et al. Lymphoma-specific genetic aberrations in microvascular endothelial cells in B-cell lymphomas. N Engl J Med 2004; 351:250–259.

    Article  PubMed  CAS  Google Scholar 

  15. Kurose K, Hoshaw-Woodard S, Adeyinka A, Lemeshow S, Watson PH, Eng C. Genetic model of multi-step breast carcinogenesis involving the epithelium and stroma: clues to tumour-microenvironment interactions. Hum Mol Genet 2001; 10:1907–1913.

    Article  PubMed  CAS  Google Scholar 

  16. Lakhani SR, Jacquemier J, Sloane JP, et al. Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 1998; 90:1138–1145.

    Article  PubMed  CAS  Google Scholar 

  17. Moinfar F, Man YG, Arnould L, Bratthauer GL, Ratschek M, Tavassoli FA. Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res 2000; 60:2562–2566.

    PubMed  CAS  Google Scholar 

  18. Banchereau J, Briere F, Caux C, et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000; 18:767–811.

    Article  PubMed  CAS  Google Scholar 

  19. Bhardwaj N. Processing and presentation of antigens by dendritic cells: implications for vaccines. Trends Mol Med 2001; 7:388–394.

    Article  PubMed  CAS  Google Scholar 

  20. Steinman RM, Turley S, Mellman I, Inaba K. The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med 2000; 191:411–416.

    Article  PubMed  CAS  Google Scholar 

  21. Yang L, Carbone DP. Tumor-host immune interactions and dendritic cell dysfunction. Adv Cancer Res 2004; 92:13–27.

    PubMed  CAS  Google Scholar 

  22. Yang AS, Lattime EC. Tumor-induced interleukin 10 suppresses the ability of splenic dendritic cells to stimulate CD4 and CD8 T-cell responses. Cancer Res 2003; 63:2150–2157.

    PubMed  CAS  Google Scholar 

  23. Tourkova IL, Yamabe K, Chatta G, Shurin GV, Shurin MR. NK cells mediate Flt3 ligand-induced protection of dendritic cell precursors in vivo from the inhibition by prostate carcinoma in the murine bone marrow metastasis model. J Immunother 2003; 26:468–472.

    Article  PubMed  CAS  Google Scholar 

  24. Furumoto K, Soares L, Engleman EG, Merad M. Induction of potent antitumor immunity by in situ targeting of intratumoral DCs. J Clin Invest 2004; 113:774–783.

    Article  PubMed  CAS  Google Scholar 

  25. Sallusto F, Lenig D, Mackay CR, Lanzavecchia A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med 1998; 187:875–883.

    Article  PubMed  CAS  Google Scholar 

  26. Vicari AP, Treilleux I, Lebecque S. Regulation of the trafficking of tumour-infiltrating dendritic cells by chemokines. Semin Cancer Biol 2004; 14:161–169.

    Article  PubMed  CAS  Google Scholar 

  27. Zou W, Machelon V, Coulomb-L’Hermin A, et al. Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat Med 2001; 7:1339–1346.

    Article  PubMed  CAS  Google Scholar 

  28. Bell D, Chomarat P, Broyles D, et al. In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J Exp Med 1999; 190:1417–1426.

    Article  PubMed  CAS  Google Scholar 

  29. Yang D, Chertov O, Bykovskaia SN, et al. Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 1999; 286:525–528.

    Article  PubMed  CAS  Google Scholar 

  30. Duits LA, Ravensbergen B, Rademaker M, Hiemstra PS, Nibbering PH. Expression of beta-defensin 1 and 2 mRNA by human monocytes, macrophages and dendritic cells. Immunology 2002; 106:517–525.

    Article  PubMed  CAS  Google Scholar 

  31. Conejo-Garcia JR, Benencia F, Courreges MC, et al. Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-A. Nat Med 2004; 10:950–958.

    Article  PubMed  CAS  Google Scholar 

  32. Sawaki K, Mizukawa N, Yamaai T, Yoshimoto T, Nakano M, Sugahara T. High concentration of betadefensin-2 in oral squamous cell carcinoma. Anticancer Res 2002; 22:2103–2107.

    PubMed  CAS  Google Scholar 

  33. Uehara N, Yagihashi A, Kondoh K, et al. Human beta-defensin-2 induction in Helicobacter pylori-infected gastric mucosal tissues: antimicrobial effect of overexpression. J Med Microbiol 2003; 52:41–45.

    Article  PubMed  CAS  Google Scholar 

  34. Hase K, Murakami M, Iimura M, et al. Expression of LL-37 by human gastric epithelial cells as a potential host defense mechanism against Helicobacter pylori. Gastroenterology 2003; 125:1613–1625.

    Article  PubMed  CAS  Google Scholar 

  35. Young AN, de Oliveira Salles PG, Lim SD, et al. Beta defensin-1, parvalbumin, and vimentin: a panel of diagnostic immunohistochemical markers for renal tumors derived from gene expression profiling studies using cDNA microarrays. Am J Surg Pathol 2003; 27:199–205.

    Article  PubMed  Google Scholar 

  36. Fujiwara K, Ochiai M, Ohta T, et al. Global gene expression analysis of rat colon cancers induced by a food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Carcinogenesis 2004; 25:1495–1505.

    Article  PubMed  CAS  Google Scholar 

  37. Vlahou A, Schellhammer PF, Mendrinos S, et al. Development of a novel proteomic approach for the detection of transitional cell carcinoma of the bladder in urine. Am J Pathol 2001; 158:1491–1502.

    PubMed  CAS  Google Scholar 

  38. Meyer JE, Harder J, Gorogh T, et al. Human beta-defensin-2 in oral cancer with opportunistic Candida infection. Anticancer Res 2004; 24:1025–1030.

    PubMed  CAS  Google Scholar 

  39. Halder TM, Bluggel M, Heinzel S, Pawelec G, Meyer HE, Kalbacher H. Defensins are dominant HLADR-associated self-peptides from CD34(-) peripheral blood mononuclear cells of different tumor patients (plasmacytoma, chronic myeloid leukemia). Blood 2000; 95:2890–2896.

    PubMed  CAS  Google Scholar 

  40. Vermi W, Bonecchi R, Facchetti F, et al. Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas. J Pathol 2003; 200:255–268.

    Article  PubMed  Google Scholar 

  41. Steinman RM, Hawiger D, Liu K, et al. Dendritic cell function in vivo during the steady state: a role in peripheral tolerance. Ann NY Acad Sci 2003; 987:15–25.

    Article  PubMed  CAS  Google Scholar 

  42. Groux H, Fournier N, Cottrez F. Role of dendritic cells in the generation of regulatory T cells. Semin Immunol 2004; 16:99–106.

    Article  PubMed  CAS  Google Scholar 

  43. Rutella S, Lemoli RM. Regulatory T cells and tolerogenic dendritic cells: from basic biology to clinical applications. Immunol Lett 2004; 94:11–26.

    Article  PubMed  CAS  Google Scholar 

  44. Kalinski P, Hilkens CM, Wierenga EA, Kapsenberg ML. T-cell priming by type-1 and type-2 polarized dendritic cells: the concept of a third signal. Immunol Today 1999; 20:561–567.

    Article  PubMed  CAS  Google Scholar 

  45. Levings MK, Bacchetta R, Schulz U, Roncarolo MG. The role of IL-10 and TGF-beta in the differentiation and effector function of T regulatory cells. Int Arch Allergy Immunol 2002; 129:263–276.

    Article  PubMed  CAS  Google Scholar 

  46. Clement A, Pereboev A, Curiel DT, Dong SS, Hutchings A, Thomas JM. Converting nonhuman primate dendritic cells into potent antigen-specific cellular immunosuppressants by genetic modification. Immunol Res 2002; 26:297–302.

    Article  PubMed  Google Scholar 

  47. Gabrilovich D, Ishida T, Oyama T, et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 1998; 92:4150–4166.

    PubMed  CAS  Google Scholar 

  48. Gabrilovich DI, Chen HL, Girgis KR, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 1996; 2:1096–1103.

    Article  PubMed  CAS  Google Scholar 

  49. Oyama T, Ran S, Ishida T, et al. Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol 1998; 160:1224–1232.

    PubMed  CAS  Google Scholar 

  50. Almand B, Resser JR, Lindman B, et al. Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res 2000; 6:1755–1766.

    PubMed  CAS  Google Scholar 

  51. Gabrilovich DI, Ishida T, Nadaf S, Ohm JE, Carbone DP. Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin Cancer Res 1999; 5:2963–2970.

    PubMed  CAS  Google Scholar 

  52. Conejo-Garcia JR, Buckanovich RJ, Benencia F, et al. Vascular leukocytes contribute to tumor vascularization. Blood 2004; 105:679–681.

    Article  PubMed  CAS  Google Scholar 

  53. Curiel TJ, Cheng P, Mottram P, et al. Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer. Cancer Res 2004; 64:5535–5538.

    Article  PubMed  CAS  Google Scholar 

  54. Jonuleit H, Giesecke-Tuettenberg A, Tuting T, et al. A comparison of two types of dendritic cell as adjuvants for the induction of melanoma-specific T-cell responses in humans following intranodal injection. Int J Cancer 2001; 93:243–251.

    Article  PubMed  CAS  Google Scholar 

  55. McIlroy D, Gregoire M. Optimizing dendritic cell-based anticancer immunotherapy: maturation state does have clinical impact. Cancer Immunol Immunother 2003; 52:583–591.

    Article  PubMed  Google Scholar 

  56. Dhodapkar MV, Steinman RM, Krasovsky J, Munz C, Bhardwaj N. Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med 2001; 193:233–238.

    Article  PubMed  CAS  Google Scholar 

  57. Nair S, McLaughlin C, Weizer A, Su Z, et al. Injection of immature dendritic cells into adjuvant-treated skin obviates the need for ex vivo maturation. J Immunol 2003; 171:6275–6282.

    PubMed  CAS  Google Scholar 

  58. Chomarat P, Banchereau J, Davoust J, Palucka AK. IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat Immunol 2000; 1:510–514.

    Article  PubMed  CAS  Google Scholar 

  59. Vicari AP, Chiodoni C, Vaure C, et al. Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J Exp Med 2002; 196:541–549.

    Article  PubMed  CAS  Google Scholar 

  60. Whiteside TL, Stanson J, Shurin MR, Ferrone S. Antigen-processing machinery in human dendritic cells: up-regulation by maturation and down-regulation by tumor cells. J Immunol 2004; 173:1526–1534.

    PubMed  CAS  Google Scholar 

  61. Chomarat P, Banchereau J. Interleukin-4 and interleukin-13: their similarities and discrepancies. Int Rev Immunol 1998; 17:1–52.

    PubMed  CAS  Google Scholar 

  62. Nair S, Boczkowski D, Moeller B, Dewhirst M, Vieweg J, Gilboa E. Synergy between tumor immunotherapy and antiangiogenic therapy. Blood 2003; 102:964–971.

    Article  PubMed  CAS  Google Scholar 

  63. Bedrosian I, Mick R, Xu S, et al. Intranodal administration of peptide-pulsed mature dendritic cell vaccines results in superior CD8+ T-cell function in melanoma patients. J Clin Oncol 2003; 21:3826–3835.

    Article  PubMed  CAS  Google Scholar 

  64. La Montagne JR, Fauci AS. Intradermal influenza vaccination-can less be more? N Engl J Med 2004; 351:2330–2332.

    Article  PubMed  Google Scholar 

  65. Redfield RR, Innis BL, Scott RM, Cannon HG, Bancroft WH. Clinical evaluation of low-dose intradermally administered hepatitis B virus vaccine. A cost reduction strategy. JAMA 1985; 254:3203–3206.

    Article  PubMed  CAS  Google Scholar 

  66. Frech SA, Kenney RT, Spyr CA, et al. Improved immune responses to influenza vaccination in the elderly using an immunostimulant patch. Vaccine 2005; 23:946–950.

    Article  PubMed  CAS  Google Scholar 

  67. Saika T, Satoh T, Kusaka N, et al. Route of administration influences the antitumor effects of bone marrow-derived dendritic cells engineered to produce interleukin-12 in a metastatic mouse prostate cancer model. Cancer Gene Ther 2004; 11:317–324.

    Article  PubMed  CAS  Google Scholar 

  68. Schmidt T, Ziske C, Marten A, et al. Intratumoral immunization with tumor RNA-pulsed dendritic cells confers antitumor immunity in a C57BL/6 pancreatic murine tumor model. Cancer Res 2003; 63:8962–8967.

    PubMed  CAS  Google Scholar 

  69. Ehtesham M, Kabos P, Gutierrez MA, Samoto K, Black KL, Yu JS. Intratumoral dendritic cell vaccination elicits potent tumoricidal immunity against malignant glioma in rats. J Immunother 2003; 26:107–116.

    Article  PubMed  Google Scholar 

  70. Candido KA, Shimizu K, McLaughlin JC, et al. Local administration of dendritic cells inhibits established breast tumor growth: implications for apoptosis-inducing agents. Cancer Res 2001; 61:228–236.

    PubMed  CAS  Google Scholar 

  71. Triozzi PL, Khurram R, Aldrich WA, Walker MJ, Kim JA, Jaynes S. Intratumoral injection of dendritic cells derived in vitro in patients with metastatic cancer. Cancer 2000; 89:2646–2654.

    Article  PubMed  CAS  Google Scholar 

  72. Melero I, Vile RG, Colombo MP. Feeding dendritic cells with tumor antigens: self-service buffet or a la carte? Gene Ther 2000; 7:1167–1170

    Article  PubMed  CAS  Google Scholar 

  73. Melero I, Duarte M, Ruiz J, et al. Intratumoral injection of bone-marrow derived dendritic cells engineered to produce interleukin-12 induces complete regression of established murine transplantable colon adenocarcinomas. Gene Ther 1999; 6:1779–1784.

    Article  PubMed  CAS  Google Scholar 

  74. Miller PW, Sharma S, Stolina M, et al. Intratumoral administration of adenoviral interleukin 7 genemodified dendritic cells augments specific antitumor immunity and achieves tumor eradication. Hum Gene Ther 2000; 11:53–65.

    Article  PubMed  CAS  Google Scholar 

  75. Kikuchi T, Moore MA, Crystal RG. Dendritic cells modified to express CD40 ligand elicit therapeutic immunity against preexisting murine tumors. Blood 2000; 96:91–99.

    PubMed  CAS  Google Scholar 

  76. Mazzolini G, Alfaro C, Sangro B, et al. Intratumoral injection of dendritic cells engineered to secrete interleukin-12 by recombinant adenovirus in patients with metastatic gastrointestinal carcinomas. J Clin Oncol 2004; 23:999–1010.

    Article  PubMed  CAS  Google Scholar 

  77. Liu Y, Xia D, Li F, Zheng C, Xiang J. Intratumoral administration of immature dendritic cells following the adenovirus vector encoding CD40 ligand elicits significant regression of established myeloma. Cancer Gene Ther 2004; 12:122–132.

    Article  CAS  Google Scholar 

  78. Tatsumi T, Huang J, Gooding WE, et al. Intratumoral delivery of dendritic cells engineered to secrete both interleukin (IL)-12 and IL-18 effectively treats local and distant disease in association with broadly reactive Tc1-type immunity. Cancer Res 2003; 63:6378–6386.

    PubMed  CAS  Google Scholar 

  79. Ahmed SU, Okamoto M, Oshikawa T, et al. Anti-tumor effect of an intratumoral administration of dendritic cells in combination with TS-1, an oral fluoropyrimidine anti-cancer drug, and OK-432, a streptococcal immunopotentiator: involvement of toll-like receptor 4. J Immunother 2004; 27:432–441.

    Article  PubMed  CAS  Google Scholar 

  80. Chen Z, Xia D, Bi X, et al. Combined radiation therapy and dendritic cell vaccine for treating solid tumors with liver micro-metastasis. J Gene Med 2004; 7:506–517.

    Article  CAS  Google Scholar 

  81. Teitz-Tennenbaum S, Li Q, Rynkiewicz S, et al. Radiotherapy potentiates the therapeutic efficacy of intratumoral dendritic cell administration. Cancer Res 2003; 63:8466–8475.

    PubMed  CAS  Google Scholar 

  82. Tanaka F, Yamaguchi H, Ohta M, et al. Intratumoral injection of dendritic cells after treatment of anticancer drugs induces tumor-specific antitumor effect in vivo. Int J Cancer 2002; 101:265–269.

    Article  PubMed  CAS  Google Scholar 

  83. Tong Y, Song W, Crystal RG. Combined intratumoral injection of bone marrow-derived dendritic cells and systemic chemotherapy to treat pre-existing murine tumors. Cancer Res 2001; 61:7530–7535.

    PubMed  CAS  Google Scholar 

  84. Mastrangelo MJ, Berd D, Maguire H Jr. The immunoaugmenting effects of cancer chemotherapeutic agents. Semin Oncol 1986; 13:186–194.

    PubMed  CAS  Google Scholar 

  85. Machiels JP, Reilly RT, Emens LA, et al. Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res 2001; 61:3689–3697.

    PubMed  CAS  Google Scholar 

  86. North RJ. Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. J Exp Med 1982; 155:1063–1074.

    Article  PubMed  CAS  Google Scholar 

  87. Juedes AE, Von Herrath MG. Using regulatory APCs to induce/maintain tolerance. Ann NY Acad Sci 2003; 1005:128–137.

    Article  PubMed  CAS  Google Scholar 

  88. Kalinski P, Hilkens CM, Snijders A, Snijdewint FG, Kapsenberg ML. IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. J Immunol 1997; 159:28–35.

    PubMed  CAS  Google Scholar 

  89. Kalinski P, Vieira PL, Schuitemaker JH, de Jong EC, Kapsenberg ML. Prostaglandin E(2) is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer. Blood 2001; 97:3466–3469.

    Article  PubMed  CAS  Google Scholar 

  90. Waller EK, Rosenthal H, Sagar L. DC2 effect on survival following allogeneic bone marrow transplantation. Oncology (Huntingt) 2002; 16:19–26.

    Google Scholar 

  91. Akdis CA, Blaser K. Mechanisms of interleukin-10-mediated immune suppression. Immunology 2001; 103:131–136.

    Article  PubMed  CAS  Google Scholar 

  92. Lucas PJ, Kim SJ, Melby SJ, Gress RE. Disruption of T cell homeostasis in mice expressing a T cellspecific dominant negative transforming growth factor beta II receptor. J Exp Med 2000; 191:1187–1196.

    Article  PubMed  CAS  Google Scholar 

  93. Chen W, Wahl SM. Manipulation of TGF-beta to control autoimmune and chronic inflammatory diseases. Microbes Infect 1999; 1:1367–1380.

    Article  PubMed  CAS  Google Scholar 

  94. Krammer PH. CD95’s deadly mission in the immune system. Nature 2000; 407:789–795.

    Article  PubMed  CAS  Google Scholar 

  95. Frauwirth KA, Riley JL, Harris MH, et al. The CD28 signaling pathway regulates glucose metabolism. Immunity 2002; 16:769–777.

    Article  PubMed  CAS  Google Scholar 

  96. Van Parijs L, Peterson DA, Abbas AK. The Fas/Fas ligand pathway and Bcl-2 regulate T cell responses to model self and foreign antigens. Immunity 1998; 8:265–274.

    Article  PubMed  Google Scholar 

  97. Whiteside TL, Rabinowich H. The role of Fas/FasL in immunosuppression induced by human tumors. Cancer Immunol Immunother 1998; 46:175–184.

    Article  PubMed  CAS  Google Scholar 

  98. Nagata S. Apoptosis by death factor. Cell 1997; 88:355–365.

    Article  PubMed  CAS  Google Scholar 

  99. Muzio M, Chinnaiyan AM, Kischkel FC, et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 1996; 85:817–827.

    Article  PubMed  CAS  Google Scholar 

  100. Griffith TS, Brunner T, Fletcher SM, Green DR, Ferguson TA. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 1995; 270:1189–1192.

    Article  PubMed  CAS  Google Scholar 

  101. Kauma SW, Huff TF, Hayes N, Nilkaeo A. Placental Fas ligand expression is a mechanism for maternal immune tolerance to the fetus. J Clin Endocrinol Metab 1999; 84:2188–2194.

    Article  PubMed  CAS  Google Scholar 

  102. Runic R, Lockwood CJ, Ma Y, Dipasquale B, Guller S. Expression of Fas ligand by human cytotrophoblasts: implications in placentation and fetal survival. J Clin Endocrinol Metab 1996; 81:3119–3122.

    Article  PubMed  CAS  Google Scholar 

  103. Rabinowich H, Reichert TE, Kashii Y, Gastman BR, Bell MC, Whiteside TL. Lymphocyte apoptosis induced by Fas ligand-expressing ovarian carcinoma cells. Implications for altered expression of T cell receptor in tumor-associated lymphocytes. J Clin Invest 1998; 101:2579–2588.

    PubMed  CAS  Google Scholar 

  104. Restifo NP. Not so Fas: re-evaluating the mechanisms of immune privilege and tumor escape. Nat Med 2000; 6:493–495.

    Article  PubMed  CAS  Google Scholar 

  105. Abrahams VM, Straszewski SL, Kamsteeg M, et al. Epithelial ovarian cancer cells secrete functional Fas ligand. Cancer Res 2003; 63:5573–5581.

    PubMed  CAS  Google Scholar 

  106. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002; 8:793–800.

    PubMed  CAS  Google Scholar 

  107. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001; 2:261–268.

    Article  PubMed  CAS  Google Scholar 

  108. Brown JA, Dorfman DM, Ma FR, et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol 2003; 170:1257–1266.

    PubMed  CAS  Google Scholar 

  109. Curiel TJ, Wei S, Dong H, et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 2003; 9:562–567.

    Article  PubMed  CAS  Google Scholar 

  110. Munn DH, Sharma MD, Lee JR, et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 2002; 297:1867–1870.

    Article  PubMed  CAS  Google Scholar 

  111. Munn DH, Sharma MD, Hou D, et al. Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest 2004; 114:280–290.

    Article  PubMed  CAS  Google Scholar 

  112. Lee GK, Park HJ, Macleod M, Chandler P, Munn DH, Mellor AL. Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology 2002; 107:452–460.

    Article  PubMed  CAS  Google Scholar 

  113. Munn DH, Mellor AL. IDO and tolerance to tumors. Trends Mol Med 2004; 10:15–18.

    Article  PubMed  CAS  Google Scholar 

  114. Fallarino F, Grohmann U, Vacca C, et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ 2002; 9:1069–1077.

    Article  PubMed  CAS  Google Scholar 

  115. Hsieh CS, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 2004; 21:267–277.

    Article  PubMed  CAS  Google Scholar 

  116. Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol 2003; 3:253–257.

    Article  PubMed  CAS  Google Scholar 

  117. Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004; 22:531–562.

    Article  PubMed  CAS  Google Scholar 

  118. 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; 10:942–949.

    Article  PubMed  CAS  Google Scholar 

  119. O’Garra A, Vieira P. Regulatory T cells and mechanisms of immune system control. Nat Med 2004; 10:801–805.

    Article  PubMed  CAS  Google Scholar 

  120. Woo EY, Chu CS, Goletz TJ, et al. Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 2001; 61:4766–4772.

    PubMed  CAS  Google Scholar 

  121. Iellem A, Mariani M, Lang R, et al. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J Exp Med 2001; 194:847–853.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  123. Sutmuller RP, van Duivenvoorde LM, van Elsas A, et al. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 2001; 194:823–832.

    Article  PubMed  CAS  Google Scholar 

  124. Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 2003; 100:8372–8377.

    Article  PubMed  CAS  Google Scholar 

  125. Hodi FS, Mihm MC, Soiffer RJ, et al. 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;100:4712–4717.

    Article  PubMed  CAS  Google Scholar 

  126. Frankel AE, Fleming DR, Hall PD, et al. A phase II study of DT fusion protein denileukin diftitox in patients with fludarabine-refractory chronic lymphocytic leukemia. Clin Cancer Res 2003; 9:3555–3561.

    PubMed  CAS  Google Scholar 

  127. Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002; 298:850–854.

    Article  PubMed  CAS  Google Scholar 

  128. Bauer S, Groh V, Wu J, et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 1999; 285:727–729.

    Article  PubMed  CAS  Google Scholar 

  129. Jamieson AM, Diefenbach A, McMahon CW, Xiong N, Carlyle JR, Raulet DH. The role of the NKG2D immunoreceptor in immune cell activation and natural killing. Immunity 2002; 17:19–29.

    Article  PubMed  CAS  Google Scholar 

  130. Wu J, Song Y, Bakker AB, et al. An activating immunoreceptor complex formed by NKG2D and DAP10. Science 1999; 285:730–732.

    Article  PubMed  CAS  Google Scholar 

  131. Diefenbach A, Jensen ER, Jamieson AM, Raulet DH. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 2001; 413:165–171.

    Article  PubMed  CAS  Google Scholar 

  132. Girardi M, Oppenheim DE, Steele CR, et al. Regulation of cutaneous malignancy by gammadelta T cells. Science 2001; 294:605–609.

    Article  PubMed  CAS  Google Scholar 

  133. Roberts AI, Lee L, Schwarz E, et al. NKG2D receptors induced by IL-15 costimulate CD28-negative effector CTL in the tissue microenvironment. J Immunol 2001; 167:5527–5530.

    PubMed  CAS  Google Scholar 

  134. Sutherland CL, Chalupny NJ, Schooley K, VandenBos T, Kubin M, Cosman D. UL16-binding proteins, novel MHC class I-related proteins, bind to NKG2D and activate multiple signaling pathways in primary NK cells. J Immunol 2002; 168:671–679.

    PubMed  CAS  Google Scholar 

  135. Cosman D, Mullberg J, Sutherland CL, et al. ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 2001; 14:123–133.

    Article  PubMed  CAS  Google Scholar 

  136. Conejo-Garcia JR, Benencia F, Courreges C, et al. Letal, a tumor-associated NKG2D immunoreceptor ligand, induces activation and expansion of effector immune cells. Cancer Biol Ther 2003; 2:446–451.

    PubMed  CAS  Google Scholar 

  137. Maus MV, Thomas AK, Leonard DG, et al. Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4-1BB. Nat Biotechnol 2002; 20:143–148.

    Article  PubMed  CAS  Google Scholar 

  138. Dudley ME, Wunderlich J, Nishimura MI, et al. Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma. J Immunother 2001; 24:363–373.

    Article  PubMed  CAS  Google Scholar 

  139. Groh V, Wu J, Yee C, Spies T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 2002; 419:734–738.

    Article  PubMed  CAS  Google Scholar 

  140. Wu CJ, Yang XF, McLaughlin S, et al. Detection of a potent humoral response associated with immuneinduced remission of chronic myelogenous leukemia. J Clin Invest 2000; 106:705–714.

    Article  PubMed  CAS  Google Scholar 

  141. Dranoff G. Coordinated tumor immunity. J Clin Invest 2003; 111:1116–1118.

    Article  PubMed  CAS  Google Scholar 

  142. Kidd P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev 2003; 8:223–246.

    PubMed  Google Scholar 

  143. Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001; 19:683–765.

    Article  PubMed  CAS  Google Scholar 

  144. Loercher AE, Nash MA, Kavanagh JJ, Platsoucas CD, Freedman RS. Identification of an IL-10-producing HLA-DR-negative monocyte subset in the malignant ascites of patients with ovarian carcinoma that inhibits cytokine protein expression and proliferation of autologous T cells. J Immunol 1999; 163:6251–6260.

    PubMed  CAS  Google Scholar 

  145. Gasperini S, Marchi M, Calzetti F, et al. Gene expression and production of the monokine induced by IFN-gamma (MIG), IFN-inducible T cell alpha chemoattractant (I-TAC), and IFN-gamma-inducible protein-10 (IP-10) chemokines by human neutrophils. J Immunol 1999; 162:4928–4937.

    PubMed  CAS  Google Scholar 

  146. Mach F, Sauty A, Iarossi AS, et al. Differential expression of three T lymphocyte-activating CXC chemokines by human atheroma-associated cells. J Clin Invest 1999; 104:1041–1050.

    PubMed  CAS  Google Scholar 

  147. Loetscher M, Loetscher P, Brass N, Meese E, Moser B. Lymphocyte-specific chemokine receptor CXCR3: regulation, chemokine binding and gene localization. Eur J Immunol 1998; 28:3696–3705.

    Article  PubMed  CAS  Google Scholar 

  148. Sorensen TL, Tani M, Jensen J, et al. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest 1999; 103:807–815.

    PubMed  CAS  Google Scholar 

  149. Qin S, Rottman JB, Myers P, et al. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest 1998; 101:746–754.

    PubMed  CAS  Google Scholar 

  150. Koga S, Auerbach MB, Engeman TM, Novick AC, Toma H, Fairchild RL. T cell infiltration into class II MHC-disparate allografts and acute rejection is dependent on the IFN-gamma-induced chemokine Mig. J Immunol 1999; 163:4878–4885.

    PubMed  CAS  Google Scholar 

  151. Biragyn A, Tani K, Grimm MC, Weeks S, Kwak LW. Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity. Nat Biotechnol 1999; 17:253–258.

    Article  PubMed  CAS  Google Scholar 

  152. Guironnet G, Dezutter-Dambuyant C, Vincent C, Bechetoille N, Schmitt D, Peguet-Navarro J. Antagonistic effects of IL-4 and TGF-beta1 on Langerhans cell-related antigen expression by human monocytes. J Leukoc Biol 2002; 71:845–853.

    PubMed  CAS  Google Scholar 

  153. Romagnani S. Cytokines and chemoattractants in allergic inflammation. Mol Immunol 2002; 38:881–885.

    Article  PubMed  CAS  Google Scholar 

  154. Sebastiani S, Allavena P, Albanesi C, et al. Chemokine receptor expression and function in CD4+ T lymphocytes with regulatory activity. J Immunol 2001; 166:996–1002.

    PubMed  CAS  Google Scholar 

  155. Conti I, Rollins BJ. CCL2 (monocyte chemoattractant protein-1) and cancer. Semin Cancer Biol 2004; 14:149–154.

    Article  PubMed  CAS  Google Scholar 

  156. Strieter RM, Polverini PJ, Arenberg DA, Kunkel SL. The role of CXC chemokines as regulators of angiogenesis. Shock 1995; 4:155–160.

    Article  PubMed  CAS  Google Scholar 

  157. Salcedo R, Young HA, Ponce ML, et al. Eotaxin (CCL11) induces in vivo angiogenic responses by human CCR3+ endothelial cells. J Immunol 2001; 166:7571–7578.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Research on Women’s Health and Reproduction, and Abramson Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA

    George Coukos MD, PhD & Jose-Ramon Conejo-Garcia MD, PhD

Authors
  1. George Coukos MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jose-Ramon Conejo-Garcia MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of Washington School of Medicine, Seattle, WA

    Mary L. Disis MD

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Coukos, G., Conejo-Garcia, JR. (2006). The Tumor Microenvironment. In: Disis, M.L. (eds) Immunotherapy of Cancer. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1385/1-59745-011-1:285

Download citation

Publish with us

Policies and ethics

Search

Navigation