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. 1995 Nov 1;182(5):1415–1421. doi: 10.1084/jem.182.5.1415

A reassessment of the role of B7-1 expression in tumor rejection

PMCID: PMC2192183  PMID: 7595212

Abstract

Introduction of the B7-1 gene into murine tumor cells can result in rejection of the B7-1 transductants and, in some cases, systemic immunity to subsequent challenge with the nontransduced tumor cells. These effects have been largely attributed to the function of B7-1 as a costimulator in directly activating tumor specific, major histocompatibility class I-restricted CD8+ T cells. We examined the role of B7-1 expression in the direct rejection as well as in the induction of systemic immunity to a nonimmunogenic murine tumor. B-16 melanoma cells with high levels of B7-1 expression did not grow in C57BL/6 recipient mice, while wild-type B-16 cells and cells with low B7-1 expression grew progressively within 21 d. In mixing experiments with B7-1hi and wild-type B-16 cells, tumors grew out in vivo even when a minority of cells were B7-1-. Furthermore, the occasional tumors that grew out after injection of 100% B-16 B7-1hi cells showed markedly decreased B7-1 expression. In vivo antibody depletions showed that NK1.1 and CD8+ T cells, but not CD4+ T cells, were essential for the in vivo rejection of tumors. Animals that rejected B-16 B7-1hi tumors did not develop enhanced systemic immunity against challenge with wild-type B-16 cells. These results suggest that a major role of B7-1 expression by tumors is to mediate direct recognition and killing by natural killer cells. With an intrinsically nonimmunogenic tumor, this direct killing does not lead to enhanced systemic immunity.

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Selected References

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  1. Azuma M., Cayabyab M., Buck D., Phillips J. H., Lanier L. L. Involvement of CD28 in MHC-unrestricted cytotoxicity mediated by a human natural killer leukemia cell line. J Immunol. 1992 Aug 15;149(4):1115–1123. [PubMed] [Google Scholar]
  2. Azuma M., Ito D., Yagita H., Okumura K., Phillips J. H., Lanier L. L., Somoza C. B70 antigen is a second ligand for CTLA-4 and CD28. Nature. 1993 Nov 4;366(6450):76–79. doi: 10.1038/366076a0. [DOI] [PubMed] [Google Scholar]
  3. Baskar S., Ostrand-Rosenberg S., Nabavi N., Nadler L. M., Freeman G. J., Glimcher L. H. Constitutive expression of B7 restores immunogenicity of tumor cells expressing truncated major histocompatibility complex class II molecules. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5687–5690. doi: 10.1073/pnas.90.12.5687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chen L., Ashe S., Brady W. A., Hellström I., Hellström K. E., Ledbetter J. A., McGowan P., Linsley P. S. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell. 1992 Dec 24;71(7):1093–1102. doi: 10.1016/s0092-8674(05)80059-5. [DOI] [PubMed] [Google Scholar]
  5. Chen L., McGowan P., Ashe S., Johnston J., Li Y., Hellström I., Hellström K. E. Tumor immunogenicity determines the effect of B7 costimulation on T cell-mediated tumor immunity. J Exp Med. 1994 Feb 1;179(2):523–532. doi: 10.1084/jem.179.2.523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Connor M. E., Stern P. L. Loss of MHC class-I expression in cervical carcinomas. Int J Cancer. 1990 Dec 15;46(6):1029–1034. doi: 10.1002/ijc.2910460614. [DOI] [PubMed] [Google Scholar]
  7. Correa I., Corral L., Raulet D. H. Multiple natural killer cell-activating signals are inhibited by major histocompatibility complex class I expression in target cells. Eur J Immunol. 1994 Jun;24(6):1323–1331. doi: 10.1002/eji.1830240613. [DOI] [PubMed] [Google Scholar]
  8. Correa I., Raulet D. H. Binding of diverse peptides to MHC class I molecules inhibits target cell lysis by activated natural killer cells. Immunity. 1995 Jan;2(1):61–71. doi: 10.1016/1074-7613(95)90079-9. [DOI] [PubMed] [Google Scholar]
  9. Csiba A., Whitwell H. L., Moore M. Distribution of histocompatibility and leucocyte differentiation antigens in normal human colon and in benign and malignant colonic neoplasms. Br J Cancer. 1984 Nov;50(5):699–709. doi: 10.1038/bjc.1984.239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dialynas D. P., Quan Z. S., Wall K. A., Pierres A., Quintáns J., Loken M. R., Pierres M., Fitch F. W. Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule. J Immunol. 1983 Nov;131(5):2445–2451. [PubMed] [Google Scholar]
  11. Doyle A., Martin W. J., Funa K., Gazdar A., Carney D., Martin S. E., Linnoila I., Cuttitta F., Mulshine J., Bunn P. Markedly decreased expression of class I histocompatibility antigens, protein, and mRNA in human small-cell lung cancer. J Exp Med. 1985 May 1;161(5):1135–1151. doi: 10.1084/jem.161.5.1135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dranoff G., Jaffee E., Lazenby A., Golumbek P., Levitsky H., Brose K., Jackson V., Hamada H., Pardoll D., Mulligan R. C. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3539–3543. doi: 10.1073/pnas.90.8.3539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fleming K. A., McMichael A., Morton J. A., Woods J., McGee J. O. Distribution of HLA class 1 antigens in normal human tissue and in mammary cancer. J Clin Pathol. 1981 Jul;34(7):779–784. doi: 10.1136/jcp.34.7.779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Freeman G. J., Borriello F., Hodes R. J., Reiser H., Hathcock K. S., Laszlo G., McKnight A. J., Kim J., Du L., Lombard D. B. Uncovering of functional alternative CTLA-4 counter-receptor in B7-deficient mice. Science. 1993 Nov 5;262(5135):907–909. doi: 10.1126/science.7694362. [DOI] [PubMed] [Google Scholar]
  15. Freeman G. J., Gray G. S., Gimmi C. D., Lombard D. B., Zhou L. J., White M., Fingeroth J. D., Gribben J. G., Nadler L. M. Structure, expression, and T cell costimulatory activity of the murine homologue of the human B lymphocyte activation antigen B7. J Exp Med. 1991 Sep 1;174(3):625–631. doi: 10.1084/jem.174.3.625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Freeman G. J., Gribben J. G., Boussiotis V. A., Ng J. W., Restivo V. A., Jr, Lombard L. A., Gray G. S., Nadler L. M. Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation. Science. 1993 Nov 5;262(5135):909–911. doi: 10.1126/science.7694363. [DOI] [PubMed] [Google Scholar]
  17. Greenberg P. D. Adoptive T cell therapy of tumors: mechanisms operative in the recognition and elimination of tumor cells. Adv Immunol. 1991;49:281–355. doi: 10.1016/s0065-2776(08)60778-6. [DOI] [PubMed] [Google Scholar]
  18. Huang A. Y., Golumbek P., Ahmadzadeh M., Jaffee E., Pardoll D., Levitsky H. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science. 1994 May 13;264(5161):961–965. doi: 10.1126/science.7513904. [DOI] [PubMed] [Google Scholar]
  19. Janeway C. A., Jr, Bottomly K. Signals and signs for lymphocyte responses. Cell. 1994 Jan 28;76(2):275–285. doi: 10.1016/0092-8674(94)90335-2. [DOI] [PubMed] [Google Scholar]
  20. Jenkins M. K., Johnson J. G. Molecules involved in T-cell costimulation. Curr Opin Immunol. 1993 Jun;5(3):361–367. doi: 10.1016/0952-7915(93)90054-v. [DOI] [PubMed] [Google Scholar]
  21. Kabawat S. E., Bast R. C., Jr, Welch W. R., Knapp R. C., Bhan A. K. Expression of major histocompatibility antigens and nature of inflammatory cellular infiltrate in ovarian neoplasms. Int J Cancer. 1983 Nov 15;32(5):547–554. doi: 10.1002/ijc.2910320505. [DOI] [PubMed] [Google Scholar]
  22. Koo G. C., Dumont F. J., Tutt M., Hackett J., Jr, Kumar V. The NK-1.1(-) mouse: a model to study differentiation of murine NK cells. J Immunol. 1986 Dec 15;137(12):3742–3747. [PubMed] [Google Scholar]
  23. Levitsky H. I., Lazenby A., Hayashi R. J., Pardoll D. M. In vivo priming of two distinct antitumor effector populations: the role of MHC class I expression. J Exp Med. 1994 Apr 1;179(4):1215–1224. doi: 10.1084/jem.179.4.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Linsley P. S., Brady W., Urnes M., Grosmaire L. S., Damle N. K., Ledbetter J. A. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991 Sep 1;174(3):561–569. doi: 10.1084/jem.174.3.561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ljunggren H. G., Kärre K. In search of the 'missing self': MHC molecules and NK cell recognition. Immunol Today. 1990 Jul;11(7):237–244. doi: 10.1016/0167-5699(90)90097-s. [DOI] [PubMed] [Google Scholar]
  26. López-Nevot M. A., Esteban F., Ferrón A., Gutiérrez J., Oliva M. R., Romero C., Huelin C., Ruiz-Cabello F., Garrido F. HLA class I gene expression on human primary tumours and autologous metastases: demonstration of selective losses of HLA antigens on colorectal, gastric and laryngeal carcinomas. Br J Cancer. 1989 Feb;59(2):221–226. doi: 10.1038/bjc.1989.45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. López-Nevot M. A., Garcia E., Romero C., Oliva M. R., Serrano S., Garrido F. Phenotypic and genetic analysis of HLA class I and HLA-DR antigen expression on human melanomas. Exp Clin Immunogenet. 1988;5(4):203–212. [PubMed] [Google Scholar]
  28. Malnati M. S., Peruzzi M., Parker K. C., Biddison W. E., Ciccone E., Moretta A., Long E. O. Peptide specificity in the recognition of MHC class I by natural killer cell clones. Science. 1995 Feb 17;267(5200):1016–1018. doi: 10.1126/science.7863326. [DOI] [PubMed] [Google Scholar]
  29. Melief C. J. Tumor eradication by adoptive transfer of cytotoxic T lymphocytes. Adv Cancer Res. 1992;58:143–175. doi: 10.1016/s0065-230x(08)60294-8. [DOI] [PubMed] [Google Scholar]
  30. Momburg F., Degener T., Bacchus E., Moldenhauer G., Hämmerling G. J., Möller P. Loss of HLA-A,B,C and de novo expression of HLA-D in colorectal cancer. Int J Cancer. 1986 Feb 15;37(2):179–184. doi: 10.1002/ijc.2910370203. [DOI] [PubMed] [Google Scholar]
  31. Momburg F., Ziegler A., Harpprecht J., Möller P., Moldenhauer G., Hämmerling G. J. Selective loss of HLA-A or HLA-B antigen expression in colon carcinoma. J Immunol. 1989 Jan 1;142(1):352–358. [PubMed] [Google Scholar]
  32. Mueller D. L., Jenkins M. K., Schwartz R. H. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–480. doi: 10.1146/annurev.iy.07.040189.002305. [DOI] [PubMed] [Google Scholar]
  33. Nandi D., Gross J. A., Allison J. P. CD28-mediated costimulation is necessary for optimal proliferation of murine NK cells. J Immunol. 1994 Apr 1;152(7):3361–3369. [PubMed] [Google Scholar]
  34. Natali P. G., Bigotti A., Cavaliere R., Nicotra M. R., Ferrone S. Phenotyping of lesions of melanocyte origin with monoclonal antibodies to melanoma-associated antigens and to HLA antigens. J Natl Cancer Inst. 1984 Jul;73(1):13–24. [PubMed] [Google Scholar]
  35. Natali P. G., Viora M., Nicotra M. R., Giacomini P., Bigotti A., Ferrone S. Antigenic heterogeneity of skin tumors of nonmelanocyte origin: analysis with monoclonal antibodies to tumor-associated antigens and to histocompatibility antigens. J Natl Cancer Inst. 1983 Sep;71(3):439–447. [PubMed] [Google Scholar]
  36. Sarmiento M., Glasebrook A. L., Fitch F. W. IgG or IgM monoclonal antibodies reactive with different determinants on the molecular complex bearing Lyt 2 antigen block T cell-mediated cytolysis in the absence of complement. J Immunol. 1980 Dec;125(6):2665–2672. [PubMed] [Google Scholar]
  37. Schwartz R. H. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992 Dec 24;71(7):1065–1068. doi: 10.1016/s0092-8674(05)80055-8. [DOI] [PubMed] [Google Scholar]
  38. Sentman C. L., Hackett J., Jr, Kumar V., Bennett M. Identification of a subset of murine natural killer cells that mediates rejection of Hh-1d but not Hh-1b bone marrow grafts. J Exp Med. 1989 Jul 1;170(1):191–202. doi: 10.1084/jem.170.1.191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Storkus W. J., Dawson J. R. Target structures involved in natural killing (NK): characteristics, distribution, and candidate molecules. Crit Rev Immunol. 1991;10(5):393–416. [PubMed] [Google Scholar]
  40. Townsend S. E., Allison J. P. Tumor rejection after direct costimulation of CD8+ T cells by B7-transfected melanoma cells. Science. 1993 Jan 15;259(5093):368–370. doi: 10.1126/science.7678351. [DOI] [PubMed] [Google Scholar]
  41. Trinchieri G. Biology of natural killer cells. Adv Immunol. 1989;47:187–376. doi: 10.1016/S0065-2776(08)60664-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Yu Y. Y., Kumar V., Bennett M. Murine natural killer cells and marrow graft rejection. Annu Rev Immunol. 1992;10:189–213. doi: 10.1146/annurev.iy.10.040192.001201. [DOI] [PubMed] [Google Scholar]
  43. van den Ingh H. F., Ruiter D. J., Griffioen G., van Muijen G. N., Ferrone S. HLA antigens in colorectal tumours--low expression of HLA class I antigens in mucinous colorectal carcinomas. Br J Cancer. 1987 Feb;55(2):125–130. doi: 10.1038/bjc.1987.26. [DOI] [PMC free article] [PubMed] [Google Scholar]

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