Skip to main content

Advertisement

SpringerLink
Log in

Morphological appearance, content of extracellular matrix and vascular density of lung metastases predicts permissiveness to infiltration by adoptively transferred natural killer and T cells

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

Abstract

We have recently shown that adoptively transferred, IL-2-activated natural killer (A-NK) cells are able to eliminate well-established B16-F10.P1 melanoma lung metastases. However, some B16-F10.P1 lung metastases were resistant to infiltration by the A-NK cells and also resistant to the A-NK cell treatment. The infiltration-resistant (I-R) B16-F10.P1 metastases had a unique “compact” morphology compared to the “loose” morphology of the infiltration-permissive (I-P) metastases. Here, we show that I-P loose tumors and I-R compact tumors are also found in lung metastases of mouse Lewis lung carcinoma (3LL), MCA-102 sarcoma, and MC38 colon carcinoma as well as rat MADB106 mammary carcinoma origin. Furthermore, the infiltration resistance of the compact tumors is not restricted to A-NK cells, since PHA and IL-2 stimulated CD8+ T-cells (T-LAK cells) also infiltrated the compact tumors poorly. Analyses of tumors for extracellular matrix (ECM) components and PECAM-1+ vasculature, revealed that the I-R lesions are hypovascularized and contain very little laminin, collagen and fibronectin. In contrast, the I-P loose tumors are well-vascularized and they contain high amounts of ECM components. Interestingly, the distribution pattern of ECM components in the I-P loose tumors is almost identical to that of the normal lung tissue, indicating that these tumors develop around the alveolar walls which provide the loose tumors with both a supporting tissue and a rich blood supply. In conclusion, tumor infiltration by activated NK and T cells correlates with the presence of ECM components and PECAM-1+ vasculature in the malignant tissue. Thus, analysis of the distribution of ECM and vasculature in tumor biopsies may help select patients most likely to benefit from cellular adoptive immunotherapy.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

IL-2:

Interleukin-2

A-NK:

Activated natural killer

Peg:

Polyethylene glycol

NK:

Natural killer

3LL:

Lewis lung carcinoma

ECM:

Extracellular matrix

References

  1. Albertsson PA, Basse PH, Hokland M, Goldfarb RH, Nagelkerke JF, Nannmark U, Kuppen PJ (2003) NK cells and the tumour microenvironment: implications for NK-cell function and anti-tumour activity. Trends Immunol 24:603–609

    Article  PubMed  CAS  Google Scholar 

  2. Allavena P, Bianchi G, Paganin C, Giardina G, Mantovani A (1996) Regulation of adhesion and transendothelial migration of natural killer cells. Nat Immun 15:107–116

    PubMed  Google Scholar 

  3. Aonuma M, Saeki Y, Akimoto T, Nakayama Y, Hattori C, Yoshitake Y, Nishikawa K, Shibuya M, Tanaka NG (1999) Vascular endothelial growth factor overproduced by tumour cells acts predominantly as a potent angiogenic factor contributing to malignant progression. Int J Exp Pathol 80:271–281

    Article  PubMed  CAS  Google Scholar 

  4. Basse P, Herberman RB, Nannmark U, Johansson BR, Hokland M, Wasserman K, Goldfarb RH (1991) Accumulation of adoptively transferred adherent, lymphokine-activated killer cells in murine metastases. J Exp Med 174:479–488

    Article  PubMed  CAS  Google Scholar 

  5. Basse PH, Nannmark U, Johansson BR, Herberman RB, Goldfarb RH (1991) Establishment of cell-to-cell contact by adoptively transferred adherent lymphokine-activated killer cells with metastatic murine melanoma cells. J Natl Cancer Inst 83:944–950

    Article  PubMed  CAS  Google Scholar 

  6. Burrows TD, King A, Loke YW (1995) The role of integrins in adhesion of decidual NK cells to extracellular matrix and decidual stromal cells. Cell Immunol 166:53–61

    Article  PubMed  CAS  Google Scholar 

  7. Donskov F, Basse PH, Hokland M (1996) Expression and function of LFA-1 on A-NK and T-LAK cells: role in tumor target killing and migration into tumor tissue. Nat Immun 15:134–146

    PubMed  CAS  Google Scholar 

  8. Fidler IJ (2001) Regulation of neoplastic angiogenesis. J Natl Cancer Inst Monogr 28:10–14

    PubMed  Google Scholar 

  9. Gimbrone MA Jr, Cotran RS, Leapman SB, Folkman J (1974) Tumor growth and neovascularization: an experimental model using the rabbit cornea. J Natl Cancer Inst 52:413–427

    PubMed  Google Scholar 

  10. Gunji Y, Vujanovic NL, Hiserodt JC, Herberman RB, Gorelik E (1989) Generation and characterization of purified adherent lymphokine-activated killer cells in mice. J Immunol 142:1748–1754

    PubMed  CAS  Google Scholar 

  11. Guo P, Fang Q, Tao HQ, Schafer CA, Fenton BM, Ding I, Hu B, Cheng SY (2003) Overexpression of vascular endothelial growth factor by MCF-7 breast cancer cells promotes estrogen-independent tumor growth in vivo. Cancer Res 63:4684–4691

    PubMed  CAS  Google Scholar 

  12. Hokland M, Kjaergaard J, Kuppen PJ, Nannmark U, Agger R, Hokland P, Basse P (1999) Endogenous and adoptively transferred A-NK and T-LAK cells continuously accumulate within murine metastases up to 48 h after inoculation. In Vivo 13:199–204

    PubMed  CAS  Google Scholar 

  13. Kjaergaard J, Hokland M, Nannmark U, Hokland P, Basse P (1998) Infiltration patterns of short- and long-term cultured A-NK and T-LAK cells following adoptive immunotherapy. Scand J Immunol 47:532–540

    Article  PubMed  CAS  Google Scholar 

  14. Kjaergaard J, Peng L, Cohen PA, Shu S (2003) Therapeutic efficacy of adoptive immunotherapy is predicated on in vivo antigen-specific proliferation of donor T cells. Clin Immunol 108:8–20

    Article  PubMed  CAS  Google Scholar 

  15. Kjaergaard J, Shu S (1999) Tumor infiltration by adoptively transferred T cells is independent of immunologic specificity but requires down-regulation of L-selectin expression. J Immunol 163:751–759

    PubMed  CAS  Google Scholar 

  16. Kuppen PJ, Basse PH, Goldfarb RH, Van De Velde CJ, Fleuren GJ, Eggermont AM (1994) The infiltration of experimentally induced lung metastases of colon carcinoma CC531 by adoptively transferred interleukin-2-activated natural killer cells in Wag rats. Int J Cancer 56:574–579

    Article  PubMed  CAS  Google Scholar 

  17. Macias C, Ballester JM, Hernandez P (2000) Expression and functional activity of the very late activation antigen-4 molecule on human natural killer cells in different states of activation. Immunology 100:77–83

    Article  PubMed  CAS  Google Scholar 

  18. McLeskey SW, Tobias CA, Vezza PR, Filie AC, Kern FG, Hanfelt J (1998) Tumor growth of FGF or VEGF transfected MCF-7 breast carcinoma cells correlates with density of specific microvessels independent of the transfected angiogenic factor. Am J Pathol 153:1993–2006

    PubMed  CAS  Google Scholar 

  19. Melder RJ, Rosenfeld CS, Herberman RB, Whiteside TL (1989) Large-scale preparation of adherent lymphokine-activated killer (A-LAK) cells for adoptive immunotherapy in man. Cancer Immunol Immunother 29:67–73

    Article  PubMed  CAS  Google Scholar 

  20. Nannmark U, Hokland ME, Agger R, Christiansen M, Kjaergaard J, Goldfarb RH, Bagge U, Unger M, Johansson BR, Albertsson PA, Basse PH (2000) Tumor blood supply and tumor localization by adoptively transferred IL- 2 activated natural killer cells. In Vivo 14:651–658

    PubMed  CAS  Google Scholar 

  21. Nannmark U, Johansson BR, Bryant JL, Unger ML, Hokland ME, Goldfarb RH, Basse PH (1995) Microvessel origin and distribution in pulmonary metastases of B16 melanoma: implication for adoptive immunotherapy. Cancer Res 55:4627–4632

    PubMed  CAS  Google Scholar 

  22. Ribeiro U, Jr., Basse PH, Rosenstein M, Safatle-Ribeiro AV, Alhallak S, Goldfarb RH, Posner MC (1997) Retention of adoptively transferred interleukin-2-activated natural killer cells in tumor tissue. Anticancer Res 17:1115–1123

    PubMed  CAS  Google Scholar 

  23. Ribeiro U Jr, Whiteside TL, Basse PH, Safatle-Ribeiro AV, Huneke CE, Posner MC (1999) Activated natural killer cell tumor retention and cytokine production in colon tumor using a tissue-isolated model. J Surg Res 82:78–87

    Article  PubMed  CAS  Google Scholar 

  24. Somersalo K (1996) Migratory functions of natural killer cells. Nat Immun 15:117–133

    PubMed  Google Scholar 

  25. van Deventer HW, Serody JS, McKinnon KP, Clements C, Brickey WJ, Ting JP (2002) Transfection of macrophage inflammatory protein 1 alpha into B16 F10 melanoma cells inhibits growth of pulmonary metastases but not subcutaneous tumors. J Immunol 169:1634–1639

    PubMed  Google Scholar 

  26. Vujanovic NL, Herberman RB, Maghazachi AA, Hiserodt JC (1988) Lymphokine-activated killer cells in rats. III. A simple method for the purification of large granular lymphocytes and their rapid expansion and conversion into lymphokine-activated killer cells. J Exp Med 167:15–29

    Article  PubMed  CAS  Google Scholar 

  27. Yang Q, Hokland ME, Bryant JL, Zhang Y, Nannmark U, Watkins SC, Goldfarb RH, Herberman RB, Basse PH (2003) Tumor-localization by adoptively transferred, interleukin-2-activated NK cells leads to destruction of well-established lung metastases. Int J Cancer 105:512–519

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the US-NIH (grants no. RO1CA87672 and R01CA104560) and the American Cancer Society (grant no. RPG-00-221-01-CDD) to P.H.B and in part by the King Gustav V Jubilee Clinic Cancer Research Foundation to PA and UN. We thank Ms. Patricia Rice and Mrs. Lisa Bailey for excellent technical assistance.

Author information

Authors and Affiliations

  1. University of Pittsburgh Cancer Institute, Hillman Cancer Center G17a, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA

    Q. Yang, S. Goding, T. Carlos & P. H. Basse

  2. University of Leiden, Leiden, Holland

    M. Hagenaars & P. Kuppen

  3. Department of Oncology, Sahlgren University Hospital, Göteborg, Sweden

    P. Albertsson

  4. University of Göteborg, Göteborg, Sweden

    U. Nannmark

  5. Institute of Medical Microbiology, University of Aarhus, Aarhus, Denmark

    M. E. Hokland

Authors
  1. Q. Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Goding
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Hagenaars
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T. Carlos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. Albertsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P. Kuppen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. U. Nannmark
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M. E. Hokland
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P. H. Basse
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. H. Basse.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, Q., Goding, S., Hagenaars, M. et al. Morphological appearance, content of extracellular matrix and vascular density of lung metastases predicts permissiveness to infiltration by adoptively transferred natural killer and T cells. Cancer Immunol Immunother 55, 699–707 (2006). https://doi.org/10.1007/s00262-005-0043-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-005-0043-4

Keywords

Search

Navigation