Skip to main content

Advertisement

SpringerLink
Log in

Colorectal carcinoma-derived fibroblasts modulate natural killer cell phenotype and antitumor cytotoxicity

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Substantial evidence indicates that cancer-associated fibroblasts (CAFs) are critical components in the process of cancer progression. However, the role of CAFs in the immunopathogenesis of human cancer remains elusive. In this study, we demonstrate that purified colorectal carcinoma-derived fibroblasts exhibit activated phenotypes characterized by substantial α-smooth muscle actin expression. These CAFs sharply suppress natural killer (NK) cell functions in co-culture experiments. In contrast, normal skin fibroblasts had only a minimal effect on NK cell phenotype and function. Moreover, we demonstrated that prostaglandin E2 (PGE2) was released by fibroblasts in co-culture experiments. Thus, the functional modulation of NK cells by CAFs may represent a novel mechanism linking the pro-inflammatory response to immune tolerance within the tumor milieu.

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

Similar content being viewed by others

Abbreviations

CAFs:

Cancer-associated fibroblasts

NK cell:

Natural killer cell

PGE2:

Prostaglandin E2

PI:

Propidium iodide

FSP:

Fibroblast surface protein

LAC:

Leukocyte activation cocktail

HFs:

Healthy donor fibroblasts

References

  1. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6(5):392–401.

    Article  PubMed  CAS  Google Scholar 

  2. Kuang DM, Zhao Q, Peng C, Xu J, Zhang JP, Wu C, et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med. 2009;206(6):1327–37.

    Article  PubMed  CAS  Google Scholar 

  3. Crawford Y, Kasman I, Yu L, Zhong C, Wu X, Modrusan Z, et al. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell. 2009;15(1):21–34.

    Article  PubMed  CAS  Google Scholar 

  4. Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H, et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell. 2004;6(1):17–32.

    Article  PubMed  CAS  Google Scholar 

  5. Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 1999;59(19):5002–11.

    PubMed  CAS  Google Scholar 

  6. Littlepage LE, Egeblad M, Werb Z. Coevolution of cancer and stromal cellular responses. Cancer Cell. 2005;7(6):499–500.

    Article  PubMed  CAS  Google Scholar 

  7. Pietras K, Pahler J, Bergers G, Hanahan D. Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med. 2008;5(1):e19.

    Article  PubMed  Google Scholar 

  8. Popov A, Schultze JL. IDO-expressing regulatory dendritic cells in cancer and chronic infection. J Mol Med. 2008;86(2):145–60.

    Article  PubMed  CAS  Google Scholar 

  9. Cerwenka A, Lanier LL. Natural killer cells, viruses and cancer. Nat Rev Immunol. 2001;1(1):41–9.

    Article  PubMed  CAS  Google Scholar 

  10. Kubota Y, Sunouchi K, Ono M, Sawada T, Muto T. Local immunity and metastasis of colorectal carcinoma. Dis Colon Rectum. 1992;35(7):645–50.

    Article  PubMed  CAS  Google Scholar 

  11. Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S, et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med. 2001;7(1):94–100.

    Article  PubMed  CAS  Google Scholar 

  12. Brown JR, DuBois RN. COX-2: a molecular target for colorectal cancer prevention. J Clin Oncol. 2005;23(12):2840–55.

    Article  PubMed  CAS  Google Scholar 

  13. Henry LR, Lee HO, Lee JS, Klein-Szanto A, Watts P, Ross EA, et al. Clinical implications of fibroblast activation protein in patients with colon cancer. Clin Cancer Res. 2007;13(6):1736–41.

    Article  PubMed  CAS  Google Scholar 

  14. Pradier A, Passweg J, Villard J, Kindler V. Human bone marrow stromal cells and skin fibroblasts inhibit natural killer cell proliferation and cytotoxic activity. Cell Transp. 2011;20(11):681–91.

    Google Scholar 

  15. Holt AP, Haughton EL, Lalor PF, Filer A, Buckley CD, Adams DH. Liver myofibroblasts regulate infiltration and positioning of lymphocytes in human liver. Gastroenterology. 2009;136(2):705–14.

    Article  PubMed  CAS  Google Scholar 

  16. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121(3):335–48.

    Article  PubMed  CAS  Google Scholar 

  17. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105(4):1815–22.

    Article  PubMed  CAS  Google Scholar 

  18. Balsamo M, Scordamaglia F, Pietra G, Manzini C, Cantoni C, Boitano M, et al. Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity. Proc Natl Acad Sci U S A. 2009;106(49):20847–52.

    Article  PubMed  CAS  Google Scholar 

  19. Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, et al. Innate or adaptive immunity? The example of natural killer cells. Science. 2011;331(6013):44–9.

    Google Scholar 

  20. Li T, Yang Y, Hua X, Wang G, Liu W, Jia C, et al. Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Lett. 2012;318(2):154–61.

    Google Scholar 

  21. Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature. 2004;432(7015):332–7.

    Article  PubMed  CAS  Google Scholar 

  22. Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood. 2008;111(3):1327–33.

    Article  PubMed  CAS  Google Scholar 

  23. Linnemeyer PA, Pollack SB. Prostaglandin E2-induced changes in the phenotype, morphology, and lytic activity of IL-2-activated natural killer cells. J Immunol. 1993;150(9):3747–54.

    PubMed  CAS  Google Scholar 

  24. Joshi PC, Zhou X, Cuchens M, Jones Q. Prostaglandin E2 suppressed IL-15-mediated human NK cell function through down-regulation of common gamma-chain. J Immunol. 2001;166(2):885–91.

    PubMed  CAS  Google Scholar 

  25. Zielinski CC, Gisinger C, Binder C, Mannhalter JW, Eibl MM. Regulation of NK cell activity by prostaglandin E2: the role of T cells. Cell Immunol. 1984;87(1):65–72.

    Article  PubMed  CAS  Google Scholar 

  26. van der Pouw Kraan TC, Boeije LC, Smeenk RJ, Wijdenes J, Aarden LA. Prostaglandin-E2 is a potent inhibitor of human interleukin 12 production. J Exp Med. 1995;181(2):775–79.

    Google Scholar 

  27. Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol. 2006;6(10):715–27.

    Article  PubMed  CAS  Google Scholar 

  28. Su X, Ye J, Hsueh EC, Zhang Y, Hoft DF, Peng G. Tumor microenvironments direct the recruitment and expansion of human Th17 cells. J Immunol. 2010;184(3):1630–41.

    Google Scholar 

  29. Barnas JL, Simpson-Abelson MR, Brooks SP, Kelleher RJ, Jr., Bankert RB. Reciprocal functional modulation of the activation of T lymphocytes and fibroblasts derived from human solid tumors. J Immunol. 2010;185(5):2681–92.

    Google Scholar 

  30. Kim S, Takahashi H, Lin WW, Descargues P, Grivennikov S, Kim Y, Luo JL, Karin M. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature. 2009;457(7225):102–6.

    Article  PubMed  CAS  Google Scholar 

  31. Langowski JL, Kastelein RA, Oft M. Swords into plowshares: IL-23 repurposes tumor immune surveillance. Trends Immunol. 2007;28(5):207–12.

    Article  PubMed  CAS  Google Scholar 

  32. Kuang DM, Peng C, Zhao Q, Wu Y, Chen MS, Zheng L. Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology. 2010;51(1):154–64.

    Google Scholar 

Download references

Acknowledgments

This work was supported by State 973 National Basic Research Program of China (2009CB522404), Program for New Century Excellent Talents in University (NCET-08-0583), National Natural Science Foundation of China (NSFC-30972914), State Key Projects on Infection Diseases of China (2008ZX10002-025, 026), Training Program Foundation for Innovative Talents by Sun Yat-sen University (82000-3126202).

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Hepatic Surgery, The 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    Tuanjie Li, Shuhong Yi, Wei Liu, Changchang Jia, Guoying Wang, Xuefeng Hua & Guihua Chen

  2. Guangdong Provincial Key Laboratory of Liver Disease Research, 600# Tianhe Rd, Guangzhou, 510630, China

    Tuanjie Li, Wei Liu, Changchang Jia, Yan Tai, Qi Zhang & Guihua Chen

  3. Cell-gene Therapy Translational Medicine Research Center, The 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    Qi Zhang

  4. General Surgery Department of Nanfang Hospital, Southern Medical University, Guangzhou, China

    Tuanjie Li

Authors
  1. Tuanjie Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuhong Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Changchang Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guoying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xuefeng Hua
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yan Tai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Guihua Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Qi Zhang or Guihua Chen.

Additional information

Tuanjie Li and Shuhong Yi have contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

12032_2013_663_MOESM1_ESM.tif

Figure S1. CAFs modulate the phenotype of NK cells. NK cells were cultured in IL-2 either alone or with the indicated fibroblast cell lines, Then, the phenotypes were analyzed by FACS. The results shown are representative of six separate experiments; the numbers indicate the percentages of positive cells. (TIFF 1911 kb)

12032_2013_663_MOESM2_ESM.tif

Figure S2. Intracytoplasmic analysis of the expression of granzyme B, perforin, and Ki67. NK cells derived from a representative donor were co-cultured with different fibroblasts and analyzed at Day five. The numbers indicate the percentages of positive cells. (TIFF 1346 kb)

12032_2013_663_MOESM3_ESM.tif

Figure S3. Impaired cytokine secretion of NK cells after co-culture with CAFs. NK cells cultured alone or in the presence of CAFs for five days were stimulated with LAC. Numbers indicate the percentages of TNF-α- and IFN-γ-positive cells. The results shown are representative of six separate experiments. (TIFF 374 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, T., Yi, S., Liu, W. et al. Colorectal carcinoma-derived fibroblasts modulate natural killer cell phenotype and antitumor cytotoxicity. Med Oncol 30, 663 (2013). https://doi.org/10.1007/s12032-013-0663-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-013-0663-z

Keywords

Search

Navigation