Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1992 Jun 1;175(6):1423–1431. doi: 10.1084/jem.175.6.1423

A nonimmunogenic sarcoma transduced with the cDNA for interferon gamma elicits CD8+ T cells against the wild-type tumor: correlation with antigen presentation capability

PMCID: PMC1974839  NIHMSID: NIHMS27579  PMID: 1588273

Abstract

To be recognized by CD8+ T lymphocytes, target cells must process and present peptide antigens in the context of major histocompatibility complex (MHC) class I molecules. The nonimmunogenic, low class I- expressing, methylcholanthrene (MCA)-induced murine sarcoma cell line, MCA 101, is a poor presenter of endogenously generated viral antigens to specific CD8+ T lymphocytes and cannot be used to generate tumor infiltrating lymphocytes (TIL). Since interferon gamma (IFN-gamma) has been shown to upregulate three sets of molecules important for antigen processing and presentation, we retrovirally transduced wild-type MCA 101 (101.WT) tumor with the mIFN-gamma cDNA to create the 101.NAT cell line. Unlike 101.WT, some clones of retrovirally transduced 101.NAT tumor expressed high levels of class I, and could be used to generate CD8+ TIL. More importantly, these TIL were therapeutic in vivo against established pulmonary metastases from the wild-type tumor. Although not uniformly cytotoxic amongst several separate cultures, these TIL did specifically release cytokines (IFN-gamma and tumor necrosis factor- alpha) in response to 101.WT targets. 101.WT's antigen presentation deficit was also reversed by gene modification with mIFN-gamma cDNA. 101.NAT had a greatly improved capacity to present viral antigens to CD8+ cytotoxic T lymphocytes. These findings show that a nonimmunogenic tumor, incapable of generating a CD8+ T cell immune response, could be gene-modified to generate a therapeutically useful immune response against the wild-type tumor. This strategy may be useful in developing treatments for tumor histologies not thought to be susceptible to T cell-based immunotherapy.

Full Text

The Full Text of this article is available as a PDF (926.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Asher A. L., Mulé J. J., Kasid A., Restifo N. P., Salo J. C., Reichert C. M., Jaffe G., Fendly B., Kriegler M., Rosenberg S. A. Murine tumor cells transduced with the gene for tumor necrosis factor-alpha. Evidence for paracrine immune effects of tumor necrosis factor against tumors. J Immunol. 1991 May 1;146(9):3227–3234. [PMC free article] [PubMed] [Google Scholar]
  2. Baglioni C., Nilsen T. W. Mechanisms of antiviral action of interferon. Interferon. 1983;5:23–42. [PubMed] [Google Scholar]
  3. Barth R. J., Jr, Bock S. N., Mulé J. J., Rosenberg S. A. Unique murine tumor-associated antigens identified by tumor infiltrating lymphocytes. J Immunol. 1990 Feb 15;144(4):1531–1537. [PubMed] [Google Scholar]
  4. Barth R. J., Jr, Mulé J. J., Spiess P. J., Rosenberg S. A. Interferon gamma and tumor necrosis factor have a role in tumor regressions mediated by murine CD8+ tumor-infiltrating lymphocytes. J Exp Med. 1991 Mar 1;173(3):647–658. doi: 10.1084/jem.173.3.647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brown M. G., Driscoll J., Monaco J. J. Structural and serological similarity of MHC-linked LMP and proteasome (multicatalytic proteinase) complexes. Nature. 1991 Sep 26;353(6342):355–357. doi: 10.1038/353355a0. [DOI] [PubMed] [Google Scholar]
  6. Deverson E. V., Gow I. R., Coadwell W. J., Monaco J. J., Butcher G. W., Howard J. C. MHC class II region encoding proteins related to the multidrug resistance family of transmembrane transporters. Nature. 1990 Dec 20;348(6303):738–741. doi: 10.1038/348738a0. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Dustin M. L., Rothlein R., Bhan A. K., Dinarello C. A., Springer T. A. Induction by IL 1 and interferon-gamma: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1). J Immunol. 1986 Jul 1;137(1):245–254. [PubMed] [Google Scholar]
  9. Elliott B. E., Carlow D. A., Rodricks A. M., Wade A. Perspectives on the role of MHC antigens in normal and malignant cell development. Adv Cancer Res. 1989;53:181–245. doi: 10.1016/s0065-230x(08)60282-1. [DOI] [PubMed] [Google Scholar]
  10. Falk K., Rötzschke O., Deres K., Metzger J., Jung G., Rammensee H. G. Identification of naturally processed viral nonapeptides allows their quantification in infected cells and suggests an allele-specific T cell epitope forecast. J Exp Med. 1991 Aug 1;174(2):425–434. doi: 10.1084/jem.174.2.425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fearon E. R., Pardoll D. M., Itaya T., Golumbek P., Levitsky H. I., Simons J. W., Karasuyama H., Vogelstein B., Frost P. Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response. Cell. 1990 Feb 9;60(3):397–403. doi: 10.1016/0092-8674(90)90591-2. [DOI] [PubMed] [Google Scholar]
  12. Gansbacher B., Bannerji R., Daniels B., Zier K., Cronin K., Gilboa E. Retroviral vector-mediated gamma-interferon gene transfer into tumor cells generates potent and long lasting antitumor immunity. Cancer Res. 1990 Dec 15;50(24):7820–7825. [PubMed] [Google Scholar]
  13. Glynne R., Powis S. H., Beck S., Kelly A., Kerr L. A., Trowsdale J. A proteasome-related gene between the two ABC transporter loci in the class II region of the human MHC. Nature. 1991 Sep 26;353(6342):357–360. doi: 10.1038/353357a0. [DOI] [PubMed] [Google Scholar]
  14. Gould K., Cossins J., Bastin J., Brownlee G. G., Townsend A. A 15 amino acid fragment of influenza nucleoprotein synthesized in the cytoplasm is presented to class I-restricted cytotoxic T lymphocytes. J Exp Med. 1989 Sep 1;170(3):1051–1056. doi: 10.1084/jem.170.3.1051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. Greenberg P. D., Cheever M. A., Fefer A. H-2 restriction of adoptive immunotherapy of advanced tumors. J Immunol. 1981 Jun;126(6):2100–2103. [PubMed] [Google Scholar]
  17. Hewitt H. B., Blake E. R., Walder A. S. A critique of the evidence for active host defence against cancer, based on personal studies of 27 murine tumours of spontaneous origin. Br J Cancer. 1976 Mar;33(3):241–259. doi: 10.1038/bjc.1976.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Itoh K., Platsoucas C. D., Balch C. M. Autologous tumor-specific cytotoxic T lymphocytes in the infiltrate of human metastatic melanomas. Activation by interleukin 2 and autologous tumor cells, and involvement of the T cell receptor. J Exp Med. 1988 Oct 1;168(4):1419–1441. doi: 10.1084/jem.168.4.1419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jardetzky T. S., Lane W. S., Robinson R. A., Madden D. R., Wiley D. C. Identification of self peptides bound to purified HLA-B27. Nature. 1991 Sep 26;353(6342):326–329. doi: 10.1038/353326a0. [DOI] [PubMed] [Google Scholar]
  20. Joly E., Mucke L., Oldstone M. B. Viral persistence in neurons explained by lack of major histocompatibility class I expression. Science. 1991 Sep 13;253(5025):1283–1285. doi: 10.1126/science.1891717. [DOI] [PubMed] [Google Scholar]
  21. Kalvakolanu D. V., Bandyopadhyay S. K., Harter M. L., Sen G. C. Inhibition of interferon-inducible gene expression by adenovirus E1A proteins: block in transcriptional complex formation. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7459–7463. doi: 10.1073/pnas.88.17.7459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kärre K., Ljunggren H. G., Piontek G., Kiessling R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature. 1986 Feb 20;319(6055):675–678. doi: 10.1038/319675a0. [DOI] [PubMed] [Google Scholar]
  23. Lassam N., Jay G. Suppression of MHC class I RNA in highly oncogenic cells occurs at the level of transcription initiation. J Immunol. 1989 Dec 1;143(11):3792–3797. [PubMed] [Google Scholar]
  24. LeGrue S. J., Ananthaswamy H. N., Simcik W. J. Afferent and efferent specificity in the induction and elicitation of parental cross-protective immunity by an immunogenic murine tumor variant: associative recognition of a unique tumor-specific antigen on somatic cell hybrids. Cancer Res. 1989 Sep 1;49(17):4747–4751. [PubMed] [Google Scholar]
  25. Madden D. R., Gorga J. C., Strominger J. L., Wiley D. C. The structure of HLA-B27 reveals nonamer self-peptides bound in an extended conformation. Nature. 1991 Sep 26;353(6342):321–325. doi: 10.1038/353321a0. [DOI] [PubMed] [Google Scholar]
  26. Monaco J. J., Cho S., Attaya M. Transport protein genes in the murine MHC: possible implications for antigen processing. Science. 1990 Dec 21;250(4988):1723–1726. doi: 10.1126/science.2270487. [DOI] [PubMed] [Google Scholar]
  27. Mulé J. J., Yang J. C., Afreniere R. L., Shu S. Y., Rosenberg S. A. Identification of cellular mechanisms operational in vivo during the regression of established pulmonary metastases by the systemic administration of high-dose recombinant interleukin 2. J Immunol. 1987 Jul 1;139(1):285–294. [PubMed] [Google Scholar]
  28. Ozato K., Sachs D. H. Monoclonal antibodies to mouse MHC antigens. III. Hybridoma antibodies reacting to antigens of the H-2b haplotype reveal genetic control of isotype expression. J Immunol. 1981 Jan;126(1):317–321. [PubMed] [Google Scholar]
  29. Restifo N. P., Esquivel F., Asher A. L., Stötter H., Barth R. J., Bennink J. R., Mulé J. J., Yewdell J. W., Rosenberg S. A. Defective presentation of endogenous antigens by a murine sarcoma. Implications for the failure of an anti-tumor immune response. J Immunol. 1991 Aug 15;147(4):1453–1459. [PMC free article] [PubMed] [Google Scholar]
  30. Rosenberg S. A. Immunotherapy and gene therapy of cancer. Cancer Res. 1991 Sep 15;51(18 Suppl):5074s–5079s. [PubMed] [Google Scholar]
  31. Rosenberg S. A., Packard B. S., Aebersold P. M., Solomon D., Topalian S. L., Toy S. T., Simon P., Lotze M. T., Yang J. C., Seipp C. A. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 1988 Dec 22;319(25):1676–1680. doi: 10.1056/NEJM198812223192527. [DOI] [PubMed] [Google Scholar]
  32. Rosenberg S. A., Spiess P., Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science. 1986 Sep 19;233(4770):1318–1321. doi: 10.1126/science.3489291. [DOI] [PubMed] [Google Scholar]
  33. Rötzschke O., Falk K., Deres K., Schild H., Norda M., Metzger J., Jung G., Rammensee H. G. Isolation and analysis of naturally processed viral peptides as recognized by cytotoxic T cells. Nature. 1990 Nov 15;348(6298):252–254. doi: 10.1038/348252a0. [DOI] [PubMed] [Google Scholar]
  34. Schreiber H., Ward P. L., Rowley D. A., Stauss H. J. Unique tumor-specific antigens. Annu Rev Immunol. 1988;6:465–483. doi: 10.1146/annurev.iy.06.040188.002341. [DOI] [PubMed] [Google Scholar]
  35. Smith G. L., Levin J. Z., Palese P., Moss B. Synthesis and cellular location of the ten influenza polypeptides individually expressed by recombinant vaccinia viruses. Virology. 1987 Oct;160(2):336–345. doi: 10.1016/0042-6822(87)90004-3. [DOI] [PubMed] [Google Scholar]
  36. Spies T., Bresnahan M., Bahram S., Arnold D., Blanck G., Mellins E., Pious D., DeMars R. A gene in the human major histocompatibility complex class II region controlling the class I antigen presentation pathway. Nature. 1990 Dec 20;348(6303):744–747. doi: 10.1038/348744a0. [DOI] [PubMed] [Google Scholar]
  37. Sugita K., Miyazaki J., Appella E., Ozato K. Interferons increase transcription of a major histocompatibility class I gene via a 5' interferon consensus sequence. Mol Cell Biol. 1987 Jul;7(7):2625–2630. doi: 10.1128/mcb.7.7.2625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Topalian S. L., Solomon D., Rosenberg S. A. Tumor-specific cytolysis by lymphocytes infiltrating human melanomas. J Immunol. 1989 May 15;142(10):3714–3725. [PubMed] [Google Scholar]
  39. Townsend A. R., Rothbard J., Gotch F. M., Bahadur G., Wraith D., McMichael A. J. The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell. 1986 Mar 28;44(6):959–968. doi: 10.1016/0092-8674(86)90019-x. [DOI] [PubMed] [Google Scholar]
  40. Trowsdale J., Hanson I., Mockridge I., Beck S., Townsend A., Kelly A. Sequences encoded in the class II region of the MHC related to the 'ABC' superfamily of transporters. Nature. 1990 Dec 20;348(6303):741–744. doi: 10.1038/348741a0. [DOI] [PubMed] [Google Scholar]
  41. Van Bleek G. M., Nathenson S. G. Isolation of an endogenously processed immunodominant viral peptide from the class I H-2Kb molecule. Nature. 1990 Nov 15;348(6298):213–216. doi: 10.1038/348213a0. [DOI] [PubMed] [Google Scholar]
  42. Watanabe Y., Kuribayashi K., Miyatake S., Nishihara K., Nakayama E., Taniyama T., Sakata T. Exogenous expression of mouse interferon gamma cDNA in mouse neuroblastoma C1300 cells results in reduced tumorigenicity by augmented anti-tumor immunity. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9456–9460. doi: 10.1073/pnas.86.23.9456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Weaver C. T., Hawrylowicz C. M., Unanue E. R. T helper cell subsets require the expression of distinct costimulatory signals by antigen-presenting cells. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8181–8185. doi: 10.1073/pnas.85.21.8181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Weber J. S., Jay G., Tanaka K., Rosenberg S. A. Immunotherapy of a murine tumor with interleukin 2. Increased sensitivity after MHC class I gene transfection. J Exp Med. 1987 Dec 1;166(6):1716–1733. doi: 10.1084/jem.166.6.1716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Yang J. C., Perry-Lalley D., Rosenberg S. A. An improved method for growing murine tumor-infiltrating lymphocytes with in vivo antitumor activity. J Biol Response Mod. 1990 Apr;9(2):149–159. [PubMed] [Google Scholar]
  46. van der Bruggen P., Traversari C., Chomez 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 Dec 13;254(5038):1643–1647. doi: 10.1126/science.1840703. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES