The critical role of type‐1 innate and acquired immunity in tumor immunotherapy (original) (raw)

Abstract

The discovery of a large array of tumor antigens has demonstrated that host lymphocytes can indeed recognize and destroy tumor cells as originally proposed in the cancer immunosurveillance hypothesis. Recent reports that led to the cancer immuno‐editing concept also strongly support the immunosurveillance hypothesis, and they further indicate that the host immune system plays a critical role not only in promoting host protection against cancer but also in selecting tumors that can better escape from immune attack. Thus, it is now clear that T cells have the ability to recognize and destroy spontaneously arising tumors. However, the generation of antitumor immunity is often difficult in the tumor‐bearing host because of various negative regulatory mechanisms. Here, we review our recent work on tumor immunotherapy, which utilizes the activation of type‐1 innate and/or acquired immunity as a potent strategy to overcome immunosuppression in the tumor‐bearing host. We have established a variety of tumor therapeutic protocols that aim to activate type‐1 immunity, such as tumor‐vaccine therapy with CpG encapsulated in liposomes, cell therapy using tumor‐specific Th1 cells, and gene therapy using gene‐engineered Th1 cells. We found that CpG encapsulated in liposomes stimulated IL‐12‐producing DC and induced IFN‐γ‐producing NK cells, NKT cells, and tumor‐specific CTL. Th1 cell therapy was also shown to be beneficial for acceleration of APC/Th1 cell‐cell interaction in the DLN, which was critical for inducing tumor‐specific CTL at the tumor site. Therefore, we conclude that the activation of type‐1 innate and acquired immunity is crucial for tumor immunotherapy in order to overcome strong immunosuppression in the tumor‐bearing host.

Abbreviations:

APC

antigen presenting cells

α‐GalCer

α‐galactosylceramide

CEA

carcinoembryonic antigen

clgTCR

chimeric immunoglobulin T cell receptor

CpG‐ODN

cytosine‐phosphorothioate‐guanine containing oligodeoxynucleotides

CTL

cytotoxic T cells

DC

dendritic cells

DLN

draining lymph node

IFN

interferon

IL

interleukin

mAb

monoclonal antibody

MCA

methylcholanthrene

Mo

macrophages

NK

natural killer

NKT

natural killer T

OVA

ovalbumin

RAG

recombination‐activating gene

scFv

single‐chain variable fragments

Tc

cytotoxic T

TCR

T cell receptor

TGF‐β

transforming growth factor‐β

Th

helper T

TLR

toll‐like receptor

Tr1

T regulatory‐1

TRA

tumor‐rejection antigens

TRAIL

tumor necrosis factor‐related apoptosis‐inducing ligand

Treg

regulatory T cells

References

• 1.Burnet FM. The concept of immunological surveillance. Prog Exp Tumor Res 1970; 13: 1–27. [DOI] [PubMed] [Google Scholar]
• 2.Thomas L. On immunosurveillance in human cancer. Yale J Biol Med 1982; 55: 329–33. [PMC free article] [PubMed] [Google Scholar]
• 3.Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001; 410: 1107–11. [DOI] [PubMed] [Google Scholar]
• 4.Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ, Schreiber RD. Demonstration of an interferon γ‐dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci USA 1998; 95: 7556–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 5.Smyth MJ, Crowe NY, Godfrey DI. NK cells and NKT cells collaborate in host protection from methylcholanthrene‐induced fibrosarcoma. Int Immunol 2001; 13: 459–63. [DOI] [PubMed] [Google Scholar]
• 6.Girardi M, Oppenheim DE, Steele CR, Lewis JM, Glusac E, Filler R, Hobby P, Sutton B, Tigelaar RE, Hayday AC. Regulation of cutaneous malignancy by γδ T cells. Science 2001; 294: 605–9. [DOI] [PubMed] [Google Scholar]
• 7.Hayashi T, Faustman DL. Development of spontaneous uterine tumors in low molecular mass polypeptide‐2 knockout mice. Cancer Res 2002; 62: 24–7. [PubMed] [Google Scholar]
• 8.Smyth MJ, Thia KY, Street SE, Cretney E, Trapani JA, Taniguchi M, Kawano T, Pelikan SB, Crowe NY, Godfrey DI. Differential tumor surveillance by natural killer (NK) and NKT cells. J Exp Med 2000; 191: 661–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 9.Street SE, Cretney E, Smyth MJ. Perform and interferon‐γ activities independently control tumor initiation, growth, and metastasis. Blood 2001; 97: 192–7. [DOI] [PubMed] [Google Scholar]
• 10.Enzler T, Gillessen S, Manis JP, Ferguson D, Fleming J, Alt FW, Mihm M, Dranoff G. Deficiencies of GM‐CSF and interferon γ link inflammation and cancer. J Exp Med 2003; 197: 1213–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 11.Cretney E, Takeda K, Yagita H, Glaccum M, Peschon JJ, Smyth MJ. Increased susceptibility to tumor initiation and metastasis in TNF‐related apoptosis‐inducing ligand‐deficient mice. J Immunol 2002; 168: 1356–61. [DOI] [PubMed] [Google Scholar]
• 12.Penn I. Malignant melanoma in organ allograft recipients. Transplantation 1996; 61: 274–8. [DOI] [PubMed] [Google Scholar]
• 13.Clemente CG, Mihm MC Jr, Bufalino R, Zurrida S, Collini P, Cascinelli N. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 1996; 77: 1303–10. [DOI] [PubMed] [Google Scholar]
• 14.Boon T, van der Bruggen P. Human tumor antigens recognized by T lymphocytes. J Exp Med 1996; 183: 725–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 15.Old LJ, Chen YT. New paths in human cancer serology. J Exp Med 1998; 187: 1163–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 16.Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002; 3: 991–8. [DOI] [PubMed] [Google Scholar]
• 17.Dunn GP, Old LJ, Schreiber RD. The three es of cancer immunoediting. Annu Rev Immunol 2004; 22: 329–60. [DOI] [PubMed] [Google Scholar]
• 18.Rosenberg SA. A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity 1999; 10: 281–7. [DOI] [PubMed] [Google Scholar]
• 19.Smyth MJ, Thi KY, Street SE, MacGregor D, Godfrey DJ, Trapani JA. Perforin‐mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med 2000; 192: 755–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 20.Svane IM, Engel AM, Nielsen MB, Ljunggren HG, Rygaard J, Werdelin O. Chemically induced sarcomas from nude mice are more immunogenic than similar sarcomas from congenic normal mice. Eur J Immunol 1996; 26: 1844–50. [DOI] [PubMed] [Google Scholar]
• 21.Engel AM, Svane IM, Rygaard J, Werdelin O. MCA sarcomas induced in scid mice are more immunogenic than MCA sarcomas induced in congenic, immunocompetent mice. Scand J Immunol 1997; 45: 463–70. [DOI] [PubMed] [Google Scholar]
• 22.Ikeda H, Old LJ, Schreiber RD. The roles of IFN γ in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev 2002; 13: 95–109. [DOI] [PubMed] [Google Scholar]
• 23.Yang Y, Huang CT, Huang X, Pardoll DM. Persistent Toll‐like receptor signals are required for reversal of regulatory T cell‐mediated CD8 tolerance. Nat Immunol 2004; 5: 508–15. [DOI] [PubMed] [Google Scholar]
• 24.Mosmann TR, Sad S. The expanding universe of T‐cell subsets: Thl, Th2 and more. Immunol Today 1996; 17: 138–46. [DOI] [PubMed] [Google Scholar]
• 25.Chamoto K, Kosaka A, Tsuji T, Matsuzaki J, Sato T, Takeshima T, Iwakabe K, Togashi Y, Koda T, Nishimura T. The critical role of Thl/Tcl circuit for the generation of tumor‐specific CTL during tumor eradication in vivo by Thl‐cell therapy. Cancer Sci 2003; 94: 924–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 26.Sato K, Yamashita N, Yamashita N, Baba M, Matsuyama T. Regulatory dendritic cells protect mice from murine acute graft‐versus‐host disease and leukemia relapse. Immunity 2003; 18: 367–79. [DOI] [PubMed] [Google Scholar]
• 27.Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, Kuniyasu Y, Nomura T, Toda M, Takahashi T. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 2001; 182: 18–32. [DOI] [PubMed] [Google Scholar]
• 28.Groux H, O'Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG. A CD4+ T‐cell subset inhibits antigen‐specific T‐cell responses and prevents colitis. Nature 1997; 389: 737–42. [DOI] [PubMed] [Google Scholar]
• 29.Takeda K, Kaisho T, Akira S. Toll‐like receptors. Annu Rev Immunol 2003; 21: 335–76. [DOI] [PubMed] [Google Scholar]
• 30.Trinchieri G. Interleukin‐12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 2003; 3: 133–46. [DOI] [PubMed] [Google Scholar]
• 31.Ohteki T, Fukao T, Suzue K, Maki C, Ito M, Nakamura M, Koyasu S. Inter‐leukin 12‐dependent interferon γ production by CD8α+ lymphoid dendritic cells. J Exp Med 1999; 189: 1981–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 32.Sato M, Chamoto K, Tsuji T, Iwakura Y, Togashi Y, Nishimura T. Th1 cytokine‐conditioned bone marrow‐derived dendritic cells can bypass the requirement for Th functions during the generation of CD8+ CTL. J Immunol 2001; 167: 3687–91. [DOI] [PubMed] [Google Scholar]
• 33.Kodama T, Takeda K, Shimozato O, Hayakawa Y, Atsuta M, Kobayashi K, Ito M, Yagita H, Okumura K. Perforin‐dependent NK cell cytotoxicity is sufficient for anti‐metastatic effect of IL‐12. Eur J Immunol 1999; 29: 1390–6. [DOI] [PubMed] [Google Scholar]
• 34.Hong S, Wilson MT, Serizawa I, Wu L, Singh N, Naidenko OV, Miura T, Haba T, Scherer DC, Wei J, Kronenberg M, Koezuka Y, van Kaer L. The natural killer T‐cell ligand α‐galactosylceramide prevents autoimmune diabetes in non‐obese diabetic mice. Nat Med 2001; 7: 1052–6. [DOI] [PubMed] [Google Scholar]
• 35.Terabe M, Matsui S, Noben‐Trauth N, Chen H, Watson C, Donaldson DD, Carbone DP, Paul WE, Berzofsky JA. NKT cell‐mediated repression of tumor immunosurveillance by IL‐13 and the IL‐4R‐STAT6 pathway. Nat Immunol 2000; 1: 515–20. [DOI] [PubMed] [Google Scholar]
• 36.Fujii S, Shimizu K, Kronenberg M, Steinman RM. Prolonged IFN‐γ‐producing NKT response induced with α‐galactosylceramide‐loaded DCs. Nat Immunol 2002; 3: 867–74. [DOI] [PubMed] [Google Scholar]
• 37.van der Bruggen P, Traversari C, Chomoez P, Lurquin C, de Plaen E, van den Eynde B, Knuth A, Boon T. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 1991; 254: 1643–7. [DOI] [PubMed] [Google Scholar]
• 38.Lee KH, Wang E, Nielsen MB, Wunderlich J, Migueles S, Connors M, Steinberg SM, Rosenberg SA, Marincola FM. Increased vaccine‐specific T cell frequency after peptide‐based vaccination correlates with increased susceptibility to in vitro stimulation but does not lead to tumor regression. J Immunol 1999; 163: 6292–300. [PubMed] [Google Scholar]
• 39.Kageshita T, Hirai S, Ono T, Hicklin DJ, Ferrone S. Down‐regulation of HLA class I antigen‐processing molecules in malignant melanoma: association with disease progression. Am J Pathol 1999; 154: 745–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 40.Kobie JJ, Wu RS, Kurt RA, Lou S, Adelman LK, Whitesel LJ, Ramanathapuram LV, Arteaga CL, Akporiaye ET. Transforming growth factor β inhibits the antigen‐presenting functions and antitumor activity of dendritic cell vaccines. Cancer Res 2003; 63: 1860–4. [PubMed] [Google Scholar]
• 41.Hori S, Takahashi T, Sakaguchi S. Control of autoimmunity by naturally arising regulatory CD4+ T cells. Adv Immunol 2003; 81: 331–71. [DOI] [PubMed] [Google Scholar]
• 42.Otsuji M, Kimura Y, Aoe T, Okamoto Y, Saito T. Oxidative stress by tumor‐derived macrophages suppresses the expression of CD3 ζ chain of T‐cell receptor complex and antigen‐specific T‐cell responses. Proc Natl Acad Sci USA 1996; 93: 13119–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 43.Tada T, Ohzeki S, Utsumi K, Takiuchi H, Muramatsu M, Li XF, Shimizu J, Fujiwara H, Hamaoka T. Transforming growth factor‐β‐induced inhibition of T cell function. Susceptibility difference in T cells of various phenotypes and functions and its relevance to immunosuppression in the tumor‐bearing state. J Immunol 1991; 146: 1077–82. [PubMed] [Google Scholar]
• 44.Yamamoto S, Yamamoto T, Kataoka T, Kuramoto E, Yano O, Tokunaga T. Unique palindromic sequences in synthetic oligonucleotides are required to induce IFN [correction of INF] and augment IFN‐mediated natural killer activity. J Immunol 1992; 148: 4072–6. [PubMed] [Google Scholar]
• 45.Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matumoto M, Hoshino K, Wagner H, Takeda K, Akira S. A Toll‐like receptor recognizes bacterial DNA. Nature 2000; 408: 740–5. [DOI] [PubMed] [Google Scholar]
• 46.Ahmad‐Najad P, Hacke H, Rutz M, Bauer S, Vabulas RM, Wagner H. Bacterial DNA and lipopolysaccharides activate Toll‐like receptors at distinct cellular compartments. Eur J Immunol 2002; 32: 1958–68. [DOI] [PubMed] [Google Scholar]
• 47.Gursel I, Gursel M, Ishii KJ, Klinman M. Sterically stabilized cationic liposomes improve the uptake and immunostimulatory activity of CpG oligonucleotides. J Immunol 2001; 167: 3324–8. [DOI] [PubMed] [Google Scholar]
• 48.Heikenwalder M, Polymenidou M, Junt T, Sigurdson C, Wagner H, Akira S, Zinkernagel R, Aguzzi A. Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nat Med 2004; 10: 187–92. [DOI] [PubMed] [Google Scholar]
• 49.Klinman DM. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol 2004; 4: 249–59. [DOI] [PubMed] [Google Scholar]
• 50.Nishimura T, Nakui M, Sato M, Iwakabe K, Kitamura H, Sekimoto M, Ota A, Koda T, Nishimura S. The critical role of Thl‐dominant immunity in tumor immunology. Cancer Chemother Pharmacol 2000; 46: S52–61. [DOI] [PubMed] [Google Scholar]
• 51.Tepper RI, Pattengale PK, Leder P. Murine interleukin‐4 displays potent anti‐tumor activity in vivo. Cell 1989; 57: 503–12. [DOI] [PubMed] [Google Scholar]
• 52.1 Distinct role of antigen‐specific T helper type 1 (Thl) and Th2 cells in tumor eradication in vivo. J Exp Med 1999; 190: 617–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 53.Sato M, Chamoto K, Nishimura T. A novel tumor vaccine cell therapy using bone marrow‐derived dendritic cell type 1 and antigen‐specific T helper type 1 cells. Int Immunol 2003; 15: 837–43. [DOI] [PubMed] [Google Scholar]
• 54.Kessels HW, Wolkers MC, van den Boom MD, van der Valk MA, Schumacher TN. Immunotherapy through TCR gene transfer. Nat Immunol 2001; 2: 957–61. [DOI] [PubMed] [Google Scholar]
• 55.Chamoto K, Tsuji T, Funamoto H, Kosaka A, Matsuzaki J, Sato T, Abe H, Fujio K, Yamamoto K, Kitamura T, Takeshima T, Togashi Y, Nishimura T. Potentiation of tumor eradication by adoptive immunotherapy with T‐cell receptor gene‐transduced T‐helper type 1 cells. Cancer Res 2004; 64: 386–90. [DOI] [PubMed] [Google Scholar]
• 56.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 γ or ζ subunits of the immunoglobulin and T‐cell receptors. Proc Natl Acad Sci USA 1993; 90: 720–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 57.Gyobu H, Tsuji T, Suzuki Y, Ohkuri T, Chamoto K, Kuroki M, Miyoshi H, Kawarada Y, Katoh H, Takeshima T, Nishimura T. Generation and targeting of human tumor‐specific Te1 and Th1 cells transduced with a lentivirus containing a chimeric immunoglobulin T cell receptor. Cancer Res 2004; 64: 1490–5. [DOI] [PubMed] [Google Scholar]