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Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1995 May;40(3):173–181. doi: 10.1007/BF01517349

The antitumor effect of tumor-draining lymph node cells activated by both anti-CD3 monoclonal antibody and activated B cells as costimulatory-signal-providing cells

Tadao Okamoto 1, Mamoru Harada 2,✉, Yoshihiro Shinomiya 1, Goro Matsuzaki 1, Kikuo Nomoto 1
PMCID: PMC11037645  PMID: 7728776

Abstract

To establish an efficient cell-culture system for adoptive immunotherapy, we attempted to use lipopolysacharide (LPS)-activated B cells (LPS blasts) as costimulatory-signal-providing cells in the in vitro induction of antitumor effector cells. Both normal and tumor-draining lymph node cells were efficiently activated by both anti-CD3 monoclonal antibody (mAb) and LPS blasts, and subsequently expanded by a low dose of interleukin-2 (IL-2; anti-CD3 mAb and LPS blasts/IL-2). The expanded cells were predominantly CD8+ T cells and showed a low level of tumor-specific cytotoxic T lymphocyte (CTL) activity. The adoptive transfer of B16-melanoma-draining lymph node cells expanded by anti-CD3 mAb and LPS blasts/IL-2 showed significant antitumor effect against the established metastases of B16 in combination with intraperitoneal injections of IL-2. This treatment cured all B16-bearing mice. In addition, these mice also showed tumorspecific protective immunity against B16 at the rechallenge. Considering that activated B cells express several kinds of costimulatory molecules, these findings thus indicate an efficacy of costimulation that is derived from activated B cells for the in vitro induction of tumor-specific CTL, in co-operation with anti-CD3 mAb. The culture system presented here may thus be therapeutically useful, providing potent effectors for adoptive immunotherapy against various types of cancer.

Key words: Adoptive immunotherapy, costimulation, Activated B cells, Anti-CD3 mAb

References

  • 1.Azuma M, Cayabyab M, Muck D, Phillips J, Lanier LL. CD28 interaction with B7 costimulates primary allogeneic proliferative responses and cytotoxicity mediated by smallo, resting T lymphocytes. J Exp Med. 1992;175:353. doi: 10.1084/jem.175.2.353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Azuma M, Ito D, Yagita H, Okumura K, Phillips JH, Lanier LL, Somoda C. B70 antigen is a second ligand for CTLA-4 and CD28. Nature. 1993;366:76. doi: 10.1038/366076a0. [DOI] [PubMed] [Google Scholar]
  • 3.Chen L, Ashe S, Brady WA, Hellström KE, Ledbetter JA, McGowan P, Linsley PS. costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocytes molecules CD28 and CTLA-4. Cell. 1992;71:1093. doi: 10.1016/s0092-8674(05)80059-5. [DOI] [PubMed] [Google Scholar]
  • 4.Chen L, Linsley PS, Hellström KE. Costimulation of T cells for tumor immunity. Immunol Today. 1993;14:483. doi: 10.1016/0167-5699(93)90262-J. [DOI] [PubMed] [Google Scholar]
  • 5.Damle NK, Klussman K, Linsley PS, Aruffo A, Ledbetter JA. Differential regulatory effects of intercellular adhesion molecule-1 on costimulation by the CD28 counter-receptor B7. J Immunol. 1992;149:2541. [PubMed] [Google Scholar]
  • 6.Fearon ER, Pardoll DM, Itaya T, Golumbek P, Levitsky HI, Simons JW, Karasuyama H, Vogelstein B, Frost P. Interleukin-2 production of an antitumor response. Cell. 1990;60:397. doi: 10.1016/0092-8674(90)90591-2. [DOI] [PubMed] [Google Scholar]
  • 7.Fraser JD, Irving BA, Crabtree GR, Weiss A. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. Science. 1991;251:313. [PubMed] [Google Scholar]
  • 8.Freeman GJ, Freeman AS, Segil JM, Lee G, Whiteman JF, Nadler LM. B7, a new member of the Ig superfamily with unique expression on activated and neoplastic B cells. J Immunol. 1989;143:2714. [PubMed] [Google Scholar]
  • 9.Freeman GJ, Gribben JG, Boussiotis VA, Ng JW, Restivo VA, Jr, Lombard LA, Gray GS, Nadler LM. Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation. Science. 1993;262:909. doi: 10.1126/science.7694363. [DOI] [PubMed] [Google Scholar]
  • 10.Greenberg PD. Adoptive T cell therapy of tumors: mechanisms operative in the recognition and elimination of tumor cells. Adv Immunol. 1991;49:281. doi: 10.1016/s0065-2776(08)60778-6. [DOI] [PubMed] [Google Scholar]
  • 11.Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin-2 activated autologous human peripheral blood lymphocytes. J Exp Med. 1982;155:1823. doi: 10.1084/jem.155.6.1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Jenkins MK, Taylor PS, Norton SD, Urdhl KB. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J Immunol. 1991;147:2461. [PubMed] [Google Scholar]
  • 13.Kurosawa S, Matsuzaki G, Harada M, Ando T, Nomoto K. Early appearance and activation of natural killer cells in tumorinfiltrating lymphoid cells during tumor development. Eur J Immunol. 1993;23:1029. doi: 10.1002/eji.1830230507. [DOI] [PubMed] [Google Scholar]
  • 14.Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991;174:561. doi: 10.1084/jem.174.3.561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Liu Y, Janeway CA., Jr Microbial induction of co-stimulatory activity for CD4 T-cell growth. Int Immunol. 1991;3:323. doi: 10.1093/intimm/3.4.323. [DOI] [PubMed] [Google Scholar]
  • 16.Liu Y, Jones B, Aruffo A, Sullivan KM, Linsley PS, Janeway CA., Jr Heat-stable antigen is a costimulatory molecule for CD4 T cell growth. J Exp Med. 1992;175:437. doi: 10.1084/jem.175.2.437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Liu Y, Jones B, Brady W, Janeway CA, Jr, Linsley PS. Costimulation of murine CD4 T cell growth: cooperation between B7 and heat-stable antigen. Eur J Immunol. 1992;22:2855. doi: 10.1002/eji.1830221115. [DOI] [PubMed] [Google Scholar]
  • 18.Nores GA, Dohi T, Taniguchi M, Hakomori S. Densitydependent recognition of cell surface GM3 lactone as a possible immunogen; requirements for tumor associated antigen and immunogen. J Immunol. 1987;139:3171. [PubMed] [Google Scholar]
  • 19.North RJ. Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. J Exp Med. 1982;5:1063. doi: 10.1084/jem.155.4.1063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Rosenberg SA, Spiess PJ, Lanreniere R. A new approach to the adoptive immunotherapy of cancer with tumor infiltrating lymphocytes. Science. 1986;233:1318. doi: 10.1126/science.3489291. [DOI] [PubMed] [Google Scholar]
  • 21.Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan M, Robertson C, Lee RE, Rubin JT, Seipp CA, Simpson CG, White DE. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med. 1987;316:889. doi: 10.1056/NEJM198704093161501. [DOI] [PubMed] [Google Scholar]
  • 22.Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Schwartzentruber D, Wei JP, White DE. Immunotherapy of patients with metastatic melanoma using tumor-infiltrating lymphocytes and interleukin-2: preliminary report. N Engl J Med. 1988;319:1676. doi: 10.1056/NEJM198812223192527. [DOI] [PubMed] [Google Scholar]
  • 23.Schwartz RH. Acquisition of immunological self-tolerance. Cell. 1989;57:1073. doi: 10.1016/0092-8674(89)90044-5. [DOI] [PubMed] [Google Scholar]
  • 24.Schwartz RH. A cell culture model for T lymphocyte clonal anergy. Science. 1990;248:1349. doi: 10.1126/science.2113314. [DOI] [PubMed] [Google Scholar]
  • 25.Shu S, Chou T, Rosenberg SA. In vitro sensitization and expansion with viable tumor cells and interleukin 2 in the generation of specific therpeutic effector cells. J Immunol. 1986;136:3891. [PubMed] [Google Scholar]
  • 26.Shu S, Chou T, Rosenberg SA. In vitro differentiation of T cells capable of mediating the regression of established syngeneic tumors in mice. Cancer Res. 1987;47:1354. [PubMed] [Google Scholar]
  • 27.Tada T, Sano H, Sato S, Shima J, Fujiwara H, Hamaoka T. Immune dysfunction expressed selectively on L3T4+ T cells in the tumor-bearing state. Leukoc Biol. 1990;47:149. doi: 10.1002/jlb.47.2.149. [DOI] [PubMed] [Google Scholar]
  • 28.Tada T, Ohzeki S, Utsumi K, Takiuchi H, Muramatsu M, Li XL, Shimizu J, Fujiwara H, Hamaoka T. Transforming growth factor-β-induced inhibition of various phenotypes and functions and its relevance to immunosuppression in the tumor-bearing state. J Immunol. 1991;146:1077. [PubMed] [Google Scholar]
  • 29.Townsend SE, Allison JP. Tumor rejection after direct costimulation of CD8+ T cells by B7-transfected melanoma cells. Science. 1993;259:368. doi: 10.1126/science.7678351. [DOI] [PubMed] [Google Scholar]
  • 30.Yoshizawa H, Chang AE, Shu S. Specific adoptive immunotherapy mediated by tumor-draining lymph node cells sequentially activated with anti-CD3 and IL-2. J Immunol. 1991;141:729. [PubMed] [Google Scholar]
  • 31.Yoshizawa H, Chang AE, Shu S. Cellular interactions in effector cell generation and tumor regression mediated by anti-CD3/inteleukin 2-activated tumor-draining lymph node cells. Cancer Res. 1992;52:1129. [PubMed] [Google Scholar]

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