Skip to main content
NCBI home page
Protein & Cell logoLink to Protein & Cell
. 2012 Jun 20;3(6):441–449. doi: 10.1007/s13238-012-2044-3

The tumor immunosuppressive microenvironment impairs the therapy of anti-HER2/neu antibody

Meng Xu 1,2, Xuexiang Du 1,2, Mingyue Liu 1,2, Sirui Li 1,2, Xiaozhu Li 1, Yang-Xin Fu 1,3,✉, Shengdian Wang 1,✉
PMCID: PMC4875483  PMID: 22717982

Abstract

It has been well established that immune surveillance plays critical roles in preventing the occurrence and progression of tumor. More and more evidence in recent years showed the host anti-tumor immune responses also play important roles in the chemotherapy and radiotherapy of cancers. Our previous study found that tumor- targeting therapy of anti-HER2/neu mAb is mediated by CD8+ T cell responses. However, we found here that enhancement of CD8+ T cell responses by combination therapy with IL-15R/IL-15 fusion protein or anti-CD40, which are strong stimultors for T cell responses, failed to promote the tumor therapeutic effects of anti-HER2/neu mAb. Analysis of tumor microenviornment showed that tumor tissues were heavily infiltrated with the immunosuppressive macrophages and most tumor infiltrating T cells, especially CD8+ T cells, expressed high level of inhibitory co-signaling receptor PD-1. These data suggest that tumor microenvironment is dominated by the immunosuppressive strategies, which thwart anti-tumor immune responses. Therefore, the successful tumor therapy should be the removal of inhibitory signals in the tumor microenvironment in combination with other therapeutic strategies.

Keywords: anti-HER2/neu antibody, CD8+ T cells, tumor microenvironment, tumor therapy, immune suppression

Contributor Information

Yang-Xin Fu, Email: yxfu@bsd.uchicago.edu.

Shengdian Wang, Email: sdwang@moon.ibp.ac.cn.

References

  1. Apetoh L., Ghiringhelli F., Tesniere A., Obeid M., Ortiz C., Criollo A., Mignot G., Maiuri M.C., Ullrich E., Saulnier P., et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13:1050–1059. doi: 10.1038/nm1622. [DOI] [PubMed] [Google Scholar]
  2. Beatty G.L., Chiorean E.G., Fishman M.P., Saboury B., Teitelbaum U.R., Sun W., Huhn R.D., Song W., Li D., Sharp L.L., et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331:1612–1616. doi: 10.1126/science.1198443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Donkor M.K., Sarkar A., Savage P.A., Franklin R.A., Johnson L.K., Jungbluth A.A., Allison J.P., Li M.O. T cell surveillance of oncogene-induced prostate cancer is impeded by T cell-derived TGF-beta1 cytokine. Immunity. 2011;35:123–134. doi: 10.1016/j.immuni.2011.04.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dubois S., Patel H.J., Zhang M., Waldmann T.A., Muller J.R. Preassociation of IL-15 with IL-15R alpha-IgG1-Fc enhances its activity on proliferation of NK and CD8+/CD44high T cells and its antitumor action. J Immunol. 2008;180:2099–2106. doi: 10.4049/jimmunol.180.4.2099. [DOI] [PubMed] [Google Scholar]
  5. Epardaud M., Elpek K.G., Rubinstein M.P., Yonekura A.R., Bellemare-Pelletier A., Bronson R., Hamerman J.A., Goldrath A.W., Turley S.J. Interleukin-15/interleukin-15R alpha complexes promote destruction of established tumors by reviving tumor-resident CD8+ T cells. Cancer Res. 2008;68:2972–2983. doi: 10.1158/0008-5472.CAN-08-0045. [DOI] [PubMed] [Google Scholar]
  6. Ferris R.L., Jaffee E.M., Ferrone S. Tumor antigen-targeted, monoclonal antibody-based immunotherapy: clinical response, cellular immunity, and immunoescape. J Clin Oncol. 2010;28:4390–4399. doi: 10.1200/JCO.2009.27.6360. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gabrilovich D.I., Ostrand-Rosenberg S., Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012;12:253–268. doi: 10.1038/nri3175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Han K.P., Zhu X., Liu B., Jeng E., Kong L., Yovandich J.L., Vyas V.V., Marcus W.D., Chavaillaz P.A., Romero C.A., et al. IL-15:IL-15 receptor alpha superagonist complex: high-level co-expression in recombinant mammalian cells, purification and characterization. Cytokine. 2011;56:804–810. doi: 10.1016/j.cyto.2011.09.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Keir M.E., Butte M.J., Freeman G.J., Sharpe A.H. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704. doi: 10.1146/annurev.immunol.26.021607.090331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kim Y.S., Kim Y.J., Lee J.M., Kim E.K., Park Y.J., Choe S.K., Ko H.J., Kang C.Y. Functional Changes in Myeloid-Derived Suppressor Cells (MDSCs) during Tumor Growth: FKBP51 Contributes to the Regulation of the Immunosuppressive Function of MDSCs. J Immunol. 2012;188:4226–4234. doi: 10.4049/jimmunol.1103040. [DOI] [PubMed] [Google Scholar]
  11. Lee Y., Auh S.L., Wang Y., Burnette B., Meng Y., Beckett M., Sharma R., Chin R., Tu T., Weichselbaum R.R., et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood. 2009;114:589–595. doi: 10.1182/blood-2009-02-206870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lipson E.J., Drake C.G. Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. Clin Cancer Res. 2011;17:6958–6962. doi: 10.1158/1078-0432.CCR-11-1595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ma G., Pan P.Y., Eisenstein S., Divino C.M., Lowell C.A., Takai T., Chen S.H. Paired immunoglobin-like receptor-B regulates the suppressive function and fate of myeloid-derived suppressor cells. Immunity. 2011;34:385–395. doi: 10.1016/j.immuni.2011.02.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Mantovani A., Allavena P., Sica A., Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–444. doi: 10.1038/nature07205. [DOI] [PubMed] [Google Scholar]
  15. Marigo I., Dolcetti L., Serafini P., Zanovello P., Bronte V. Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev. 2008;222:162–179. doi: 10.1111/j.1600-065X.2008.00602.x. [DOI] [PubMed] [Google Scholar]
  16. Mortier E., Quemener A., Vusio P., Lorenzen I., Boublik Y., Grotzinger J., Plet A., Jacques Y. Soluble interleukin-15 receptor alpha (IL-15R alpha)-sushi as a selective and potent agonist of IL-15 action through IL-15R beta/gamma. Hyperagonist IL-15 × IL-15R alpha fusion proteins. J Biol Chem. 2006;281:1612–1619. doi: 10.1074/jbc.M508624200. [DOI] [PubMed] [Google Scholar]
  17. Park S., Jiang Z., Mortenson E.D., Deng L., Radkevich-Brown O., Yang X., Sattar H., Wang Y., Brown N.K., Greene M., et al. The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell. 2010;18:160–170. doi: 10.1016/j.ccr.2010.06.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Qian B.Z., Pollard J.W. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51. doi: 10.1016/j.cell.2010.03.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Sakuishi K., Apetoh L., Sullivan J.M., Blazar B.R., Kuchroo V.K., Anderson A.C. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207:2187–2194. doi: 10.1084/jem.20100643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Schreiber R.D., Old L.J., Smyth M.J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–1570. doi: 10.1126/science.1203486. [DOI] [PubMed] [Google Scholar]
  21. Sistigu A., Viaud S., Chaput N., Bracci L., Proietti E., Zitvogel L. Immunomodulatory effects of cyclophosphamide and implementations for vaccine design. Semin Immunopathol. 2011;33:369–383. doi: 10.1007/s00281-011-0245-0. [DOI] [PubMed] [Google Scholar]
  22. Tartour E., Pere H., Maillere B., Terme M., Merillon N., Taieb J., Sandoval F., Quintin-Colonna F., Lacerda K., Karadimou A., et al. Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy. Cancer Metastasis Rev. 2011;30:83–95. doi: 10.1007/s10555-011-9281-4. [DOI] [PubMed] [Google Scholar]
  23. Willimsky G., Czeh M., Loddenkemper C., Gellermann J., Schmidt K., Wust P., Stein H., Blankenstein T. Immunogenicity of premalignant lesions is the primary cause of general cytotoxic T lymphocyte unresponsiveness. J Exp Med. 2008;205:1687–1700. doi: 10.1084/jem.20072016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Yu P., Lee Y., Liu W., Krausz T., Chong A., Schreiber H., Fu Y.X. Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med. 2005;201:779–791. doi: 10.1084/jem.20041684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Zhou Q., Munger M.E., Veenstra R.G., Weigel B.J., Hirashima M., Munn D.H., Murphy W.J., Azuma M., Anderson A.C., Kuchroo V.K., et al. Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood. 2011;117:4501–4510. doi: 10.1182/blood-2010-10-310425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Zitvogel L., Kepp O., Kroemer G. Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol. 2011;8:151–160. doi: 10.1038/nrclinonc.2010.223. [DOI] [PubMed] [Google Scholar]

Articles from Protein & Cell are provided here courtesy of Oxford University Press

RESOURCES