Skip to main content

Advertisement

SpringerLink
Log in

In search of specific cytotoxic T lymphocytes infiltrating or accompanying human ovarian carcinoma

  • Original articles
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Summary

Lymphocytes infiltrating human ovarian carcinoma obtained directly from the tumour mass (tumour-infiltrating lymphocytes, TIL) or from the carcinomatous ascites (tumour-associated lymphocytes, TAL) were expanded in vitro in long-term cultures with interleukin-2 and tested for their specific cytolytic activity. Killing of the autologous tumour was detected only in a proportion of the patients, less frequently in TIL compared to TAL. In fact two out of ten TIL and four out of nine TAL cultures tested showed significant levels of lysis against the autologous tumour. This cytotoxic activity was not restricted to the autologous tumour, as other tumour cell lines, including non-ovarian ones, were lysed as well. The cultures that were not cytotoxic against the autologous tumour were in most cases able to lyse other tumour cell lines of ovarian or other histology. Cloning of TIL from one patient was performed: of 22 clones tested, 4 displayed higher cytotoxicity against the autologous tumour compared to the uncloned population and 3 out of these 4 did not kill an irrelevant carcinoma cell line. In order to stimulate the expansion of putative specific effectors we performed mixed lymphocyte/tumour cultures (MLTC) with autologous or allogeneic tumour cells. No stimulation of cytotoxicity against the autologous tumour was detected after MLTC in nine different TAL populations, using autologous or allogeneic tumours as stimulators. On the contrary, peripheral blood lymphocytes from two patients after MLTC with the autologous tumour showed increased killing of the autologous and decreased killing of an allogeneic target. In conclusion TIL and TAL from ovarian carcinoma expanded in vitro with interleukin-2 usually have non-MHC-restricted cytotoxicity and variable degrees of reactivity against the autologous tumour. A preferential killing for the autologous tumour was not observed even after MLTC. These results do not exclude the existence of tumour-specific cytotoxic T lymphocytes in ovarian carcinoma; nevertheless they suggest that putative specific effectors have very low frequency and that culture techniques for expanding their growth more selectively are still to be optimized.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Allavena P, Ortaldo JR (1984) Characterization of human natural killer clones: target specificity and phenotype. J Immunol 132: 2363

    PubMed  Google Scholar 

  2. Allavena P, Zanaboni F, Rossini S, Merendino A, Bonazzi C, Vassena L, Mangioni C, Mantovani A (1986). Lymphokine activated killer activity of tumor associated and peripheral blood lymphocytes isolated from patients with ascites ovarian tumors. JNCI 77(4): 863

    PubMed  Google Scholar 

  3. Allavena P, Grandi M, D'Incalci M, Geri O, Giuliani FC, Mantovani A (1987) Human tumor cell lines with pleiotropic drug resistance are efficiently killed by interleukin-2 activated killer cells and by activated monocytes. Int J Cancer 40: 104

    PubMed  Google Scholar 

  4. Allavena P, Lo Presti P, Di Bello M, Lucchini V, Lissoni A, Zanetta G, Mangioni C, Mantovani A (1988) Proliferative response of lymphocytes from ovarian cancer patients to autologous tumor cells. Cancer Immunol Immunother 27: 69

    PubMed  Google Scholar 

  5. Anichini A, Fossati G, Parmiani G (1987) Clonal analysis of the cytolytic T cell response to human tumors. Immunol Today 8: 385

    Google Scholar 

  6. Barnd DL, Lan MS, Metzgar RS, Finn OJ (1989) Specific, major histocompatibility complex-unrestricted recognition of tumor associated mucins by human cytotoxic T-cells. Proc Natl Acad Sci USA 86: 7159

    PubMed  Google Scholar 

  7. Bast RS Jr, Feeney M, Lazarus H, Nadler LM, Colvin RB, Knapp RC (1981) Reactivity of monoclonal antibody with ovarian carcinoma. J Clin Invest 68: 1331

    PubMed  Google Scholar 

  8. Belldegrun A, Muul LM, Rosenberg SA (1988) Interleukin-2 expanded tumor infiltrating lymphocytes in human renal cell cancer: isolation, characterization and antitumor activity. Cancer Res 4: 206

    Google Scholar 

  9. Blanchard DK, Kavanagh JJ, Sinkovics JG, Cavanagh D, Hewitt SM, Djeu JY (1988) Infiltration of interleukin-2-inducible killer cells in ascitic fluid and pleural effusions of advanced cancer patients. Cancer Res 48: 6321

    PubMed  Google Scholar 

  10. Ferrini S, Biassoni R, Moretta A, Bruzzone M, Nicolin A, Moretta L (1985) Clonal analysis of T-lymphocytes isolated from ovarian carcinoma ascitic fluid. Phenotypic and functional characterization of T-cell clones capable of lysing autologous carcinoma cells. Int J Cancer 36: 337

    PubMed  Google Scholar 

  11. Grimm EA, Rosenberg SA (1984) The human lymphokine activated killer phenomenon. In: Pick E (ed) Lymphokines, vol 9, Academic Press, Orlando, p 279

    Google Scholar 

  12. Heo DS, Whiteside TL, Kanbour A, Herberman RB (1988) Lymphocytes infiltrating human ovarian tumors: I. Role of Leu-19 (NKH1)-positive recombinant interleukin-2 activated cultures of lymphocytes infiltrating human ovarian tumors. J Immunol 140: 4042

    PubMed  Google Scholar 

  13. Immai S, Kiyozuka Y, Maeda H, Noda T, Hosick HL (1990) Establishment and characterization of a human ovarian serous cystadenocarcinoma cell line that produces the tumor markers CA-125 and tissue polypeptide antigen. Oncology 47: 177

    PubMed  Google Scholar 

  14. Ioannides CG, Freedman RS, Platsoukas CD, Rashed S, Kim YP (1991) Cytotoxic T-cell clones isolated from ovarian tumor, infiltrating lymphocytes recognize multiple epitopes on autologous tumor cells. J Immunol 146: 1700

    PubMed  Google Scholar 

  15. Itoh K, Platsoukas CD, Balch CM (1988) 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 168: 1419

    PubMed  Google Scholar 

  16. Kradin RL, Lazarus DS, Dubinett SM, Gifford J, Grove B, Kurnick JT, Pretter FI, Pinto CE, Davison E, Collahan RJ, Strauss HW (1989) Tumor-infiltrating lymphocytes and interleukin-2 in treatment of advanced cancer. Lancet 1: 577

    PubMed  Google Scholar 

  17. Lotzovà E (1988) Ovarian tumor infiltrating lymphocytes: phenotype and anti-tumor activity. Nat Immun Cell Growth Regul 7: 226

    PubMed  Google Scholar 

  18. Massazza G, Tomasoni A, Lucchini V, Allavena P, Erba E, Colombo N, Mantovani A, D'Incalci M, Mangioni C, Giavazzi R (1989) Intraperitoneal and subcutaneous xenografts of human ovarian carcinoma in nude mice and their potential in experimental therapy. Int J Cancer 44: 494

    PubMed  Google Scholar 

  19. Masuho Y, Zalutsky M, Knapp RC, Bast RC (1984) Interaction of monoclonal antibodies with cell surface antigens of human ovarian carcinomas. Cancer Res 44: 2813

    PubMed  Google Scholar 

  20. Miescher S, Stoeck M, Qiao L, Barras C, Barrelet L, von Fliedner V (1988) Preferential clonogenic deficit of CD8 positive T-lymphocytes infiltrating human solid tumors. Cancer Res 48: 6992

    PubMed  Google Scholar 

  21. Miotti S, Canevari S, Mènard S, Mezzanzanica D, Porro G, Pupa SM, Regazzoni M, Tagliabue E, Colnaghi MI (1987) Characterization of human ovarian carcinoma associated antigens defined by novel monoclonal antibodies with tumor-restricted specificity. Int J Cancer 39: 297

    PubMed  Google Scholar 

  22. Muul LM, Spiess PJ, Director EP, Rosenberg SA (1987) Identification of specific cytolytic immune responses against autologous tumor in humans bearing malignant melanoma. J Immunol 138: 989

    PubMed  Google Scholar 

  23. Parmiani G (1990a) An explanation of the variable clinical response to interleukin-2 and LAK cells. Immunol Today 11: 113

    PubMed  Google Scholar 

  24. Parmiani G, Anichini A, Fossati G (1990b) Cellular immune response against autologous human malignant melanoma: are in vitro studies providing a framework for a more effective immunotherapy? J Natl Cancer Inst 82: 361

    PubMed  Google Scholar 

  25. Peri G, Polentarutti N, Sessa C, Mangioni C, Mantovani A (1981) Tumoricidal activity of macrophages isolated from human ascitic and solid ovarian carcinomas. Int J Cancer 28: 143

    PubMed  Google Scholar 

  26. Poels LG, Peters D, van Megen Y, Vooijs GP, Verheyen RNM, Willemen A, van Niekerk CC, Jap PHK, Mungyer G, Kenemans P (1986) Monoclonal antibody against human ovarian tumor associated antigens. JNCI 76: 781

    PubMed  Google Scholar 

  27. Ranges EE, Figari IS, Espevik T, Palladino MA Jr (1987) Inhibition of cytotoxic T-cell development by transforming growth factor-β and reversal by recombinant tumor necrosis factor-α. J Exp Med 166: 991

    PubMed  Google Scholar 

  28. Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT, Seipp CA, Simpson CG, White DE (1987) 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 316: 889

    PubMed  Google Scholar 

  29. Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Lotze MT, Yang JC, Seipp C, Simpson C, Carter C, Bock S, Schwartzentruber D, Wei JP, White DE (1988) Use of tumor infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. N Engl J Med 319: 1676

    PubMed  Google Scholar 

  30. Topalian SL, Solomon D, Avis FF, Chang AE, Freerkson DL, Linchan WM, Lotzo MT, Robertson CN, Seipp CA, Simon P, Simpson CG, Rosenberg SA (1988) Immunotherapy of patients with advanced cancer using tumor-infiltrating lymphocytes and recombinant interleukin-2: a pilot study. J Clin Oncol 6: 839

    PubMed  Google Scholar 

  31. Vànky F, Klein E, Stjernswärd J, Rodriguez L, Péterffy A, Steiner L, Nilsonne U (1978) Human tumor-lymphocyte interaction in vitro III: T lymphocytes in autologous tumor stimulation (ATS) Int J Cancer 22: 679

    PubMed  Google Scholar 

  32. Vose BM (1987) Activation of lymphocyte anti-tumor responses in man: effector heterogeneity and the search for immunomodulators. Cancer Metastasis Rev 5: 299

    PubMed  Google Scholar 

  33. Wang Yi Li, Lusheng S, Kanbour L, Herberman RB, Whiteside TL (1989) Lymphocytes infiltrating human ovarian tumors: synergy between tumor necrosis factor-α and interleukin-2 in the generation of CD8+ effectors from tumor infiltrating lymphocytes. Cancer Res 49: 5979

    PubMed  Google Scholar 

  34. Wersall P, Hising C, Masucci G, Pataroyo M, Pihlstedt P, Einhorn N, Mellstedt H (1990) Long-term culture of cytotoxic tumor associated lymphocytes from the ascites of ovarian carcinoma patients. Cancer J 3: 321

    Google Scholar 

  35. Wysocki LJ, Sato VL (1978) “Panning” for lymphocytes: a method for cell selection. Proc Natl Acad Sci USA 75: 2844

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Immunology, “Mario Negri” Institute, Via Eritrea, 62, 20157, Milano, Italy

    M. Apiranthitou-Drogari, C. Paganin, S. Bernasconi, A. Mantovani & P. Allavena

  2. Department of Obstetrics and Gynaecology, University of Milano, Ospedale S. Gerardo, Monza, MI, Italy

    G. Losa, A. Maneo & N. Colombo

Authors
  1. M. Apiranthitou-Drogari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Paganin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Bernasconi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Losa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Maneo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N. Colombo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Mantovani
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P. Allavena
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Apiranthitou-Drogari, M., Paganin, C., Bernasconi, S. et al. In search of specific cytotoxic T lymphocytes infiltrating or accompanying human ovarian carcinoma. Cancer Immunol Immunother 35, 289–295 (1992). https://doi.org/10.1007/BF01789337

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01789337

Key words

Search

Navigation