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Antigenic Hsp70–peptide upregulate altered cell surface MHC class I expression in TAMs and increases anti-tumor function in Dalton’s lymphoma bearing mice

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Tumor Biology

Abstract

Major histocompatibility complex (MHC) class I molecules not only provide a mechanistic framework for the cell-to-cell communication, but also possess broader biological function. Due to their ability to regulate presentation of tumor-associated antigens (TAAs), viral peptides which play an essential role in the regulation of immune responses by presenting antigenic peptides to cytotoxic T lymphocytes and by regulating cytolytic activities of immune cells. Tumor cells frequently do not express MHC class I molecules; as a result, tumor cells escape from immune surveillance. Cells surviving in tumor microenvironment are often characterized by a profound immune escape phenotype with alterations in MHC class I way of antigen processing. Cellular components of the tumor microenvironment, in particular alternatively activated M2 phenotype, are involved in tumor progression and suppression of anti-tumor immunity. Hsp70 is well recognized for its role in activating macrophages leading to enhanced production of inflammatory cytokines. It has been observed that Hsp70 derived from normal tissues do not elicit tumor immunity, while Hsp70 preparation from tumor cell associated with antigen are able to elicit tumor immunity. The finding shows that the expression of MHC class I (H2Db) drastically decreases in TAMs and Hsp70–peptide complex enhances H2Db expression in TAMs and it reverts back the suppressed function of TAMs into the M1 state of immunoregulatory phenotype that promotes tumor regression by enhanced antigen presentation.

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Abbreviations

TAMs:

Tumor-associated macrophages

MΦ:

Macrophages

HSCs:

Hematopoietic stem cells

IL:

Interleukin

HSP:

Heat shock protein

PECs:

Peritoneal exudate cells

MHC:

Major histocompatibility complex

TAAs:

Tumor-associated antigens

NMO:

Normal macrophages

References

  1. Forngaleg-Behia EB, Doseff AI. Regulation of monocytes and macrophages cell fate. Front Biosci. 2008;14:2413–31.

    Google Scholar 

  2. Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66(2):605–12.

    Article  CAS  PubMed  Google Scholar 

  3. Subauste CS, Malefyt RDW, Fuh F. Role of CD80 (B7.1) and CD86 (B7.2) in the immune response to an intracellular pathogen. J Immunol. 1998;160:1831–40.

    CAS  PubMed  Google Scholar 

  4. Nardin A, Anastado JP. Macrophage and cancer. Front Biosci. 2008;13:3494–505.

    Article  CAS  PubMed  Google Scholar 

  5. Ramachandra L, Chu RS, Askew D, Noss EH, et al. Phagocytic antigen processing and effects of microbial products on antigen processing and T-cell responses. Immunol Rev. 1999;168:217–39.

    Article  CAS  PubMed  Google Scholar 

  6. Seliger B, Maeurer MJ, Ferrone S. Antigen-processing machinery breakdown and tumour growth. Immunol Today. 2000;21:455–64.

    Article  CAS  PubMed  Google Scholar 

  7. Costello RGT, Mallet FO, Sainty D, et al. Regulation of CD80/B7-1 and CD86/B7-2 molecule expression in human primary acute myeloid leukemia and their role in allogenic immune recognition. Eur J Immunol. 1998;28:90–03.

    Article  CAS  PubMed  Google Scholar 

  8. Levin I, Klein T, Kuperman O, Segal S, Shapira J, Gal R, et al. The expression of HLA class I antigen in prostate cancer in relation to tumour differentiation and patient survival. Cancer Detect Prev. 1994;18:443–45.

    CAS  PubMed  Google Scholar 

  9. Maddalena M, Emilia A, Lisa V. HLA-dependent tumour development: a role for tumour associate macrophages? J Transl Med. 2013;11(247):1–15.

    Google Scholar 

  10. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11:889–89.

    Article  CAS  PubMed  Google Scholar 

  11. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000;164:6166–73.

    Article  CAS  PubMed  Google Scholar 

  12. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–55.

    Article  CAS  PubMed  Google Scholar 

  13. Mahoney KH, Heppner GH. Facs analysis of tumor- associated macrophages replication: differentiation between metastasis and nonmetastasic murine mammary tumor. J Leukoc Biol. 1987;41:205–11.

    CAS  PubMed  Google Scholar 

  14. Solinas G, Germano G, Mantovani A, Allavena AP, et al. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol. 2009;86:1065–73.

    Article  CAS  PubMed  Google Scholar 

  15. Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell. 2005;7:211–17.

    Article  CAS  PubMed  Google Scholar 

  16. Siveen KS, Kuttan G. Role of macrophage in tumor progression. Immunol Lett. 2009;123:97–02.

    Article  CAS  PubMed  Google Scholar 

  17. Villadangos JA, Schnorrer P, Wilson NS. Control of MHC class II antigen presentation in dendritic cells: a balance between creative and destructive forces. Immunol Rev. 2005;207:191–05.

    Article  CAS  PubMed  Google Scholar 

  18. Botond ZI, Daniel HK. Antigen presentation by Langerhans cells. Curr Opin Immunol. 2013;25:115–19.

    Article  Google Scholar 

  19. Jattela M. Heat shock proteins as cellular lifeguards. Ann Med. 1999;31:261–71.

    Article  Google Scholar 

  20. Blachere NE, Li Z, Chandawarkar RY, et al. Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytoxic T-lymphocytes response and tumor immunity. J Exp Med. 1997;186:1315–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tamura Y, Peng P, Liu K, et al. Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations. Science. 1997;278:117–20.

    Article  CAS  PubMed  Google Scholar 

  22. Udono H, Srivastava PK. Heat shock protein 70-associated peptides elicit specific cancer immunity. J Exp Med. 1993;178:1391–96.

    Article  CAS  PubMed  Google Scholar 

  23. Tokuda Y, Tsuji M, Yamazaki M, et al. Augmentation of murine tumor necrosis factor production by amphotericin B in vitro and in vivo. Antimicrob Agents Chemother. 1993;37:2228–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970;227:680–85.

    Article  CAS  PubMed  Google Scholar 

  25. Blachere NE, Li Z, Chandawarkar RY, Suto R, Jaikaria S, Basu S, et al. Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytoxic T-lymphocytes response and tumor immunity. J Exp Med. 1997;186:1315–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tamura Y, Peng P, Liu K, Daou M, Srivastava PK. Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations. Science. 1997;278:117–20.

    Article  CAS  PubMed  Google Scholar 

  27. Laugel B, Cole DK, Clement M, Wooldridge L, Price DA, Sewell AK. The multiple roles of the CD8 coreceptor in T cell biology: opportunities for the selective modulation of self-reactive cytotoxic T cells. J Leukoc Biol. 2011;90:1089–99.

    Article  CAS  PubMed  Google Scholar 

  28. Vyas JM, Van der Veen AG, Ploegh HL. The known unknowns of antigen processing and presentation. Nat Rev Immunol. 2008;8:607–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Groothuis TA, Griekspoor AC, Neijssen JJ, Herberts CA, Neefjes JJ. MHC class I alleles and their exploration of the antigen-processing machinery. Immunol Rev. 2005;207:60–76.

    Article  CAS  PubMed  Google Scholar 

  30. Nitta T, Murata S, Sasaki K, Fujii H, Ripen AM, Ishimaru N, et al. Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells. Immunity. 2010;32:29–40.

    Article  CAS  PubMed  Google Scholar 

  31. Odile B, Jean Fran OB, Heltne Z, Alain I, Philippe K, Jean D. Altered binding of regulatory factors to HLA class I enhancer sequence in human tumor cell lines lacking class I antigen expression. Proc Natl Acad Sci U S A. 1992;89:3488–92.

    Article  Google Scholar 

  32. Blades RA, Er CS, Patrick J, Keating MRCOG. Loss of Hla class i expression in prostate cancer: implications for immunotherapy. Urology. 1995;46(5):681–87.

    Article  CAS  PubMed  Google Scholar 

  33. Villadangos JA, Schnorrer P, Wilson NS. Control of MHC class II antigen presentation in dendritic cells: a balance between creative and destructive forces. Immunol Rev. 2005;207:191–05.

    Article  CAS  PubMed  Google Scholar 

  34. Juergen B, Simon J, Barbara S. The role of classical and non-classical HLA class I antigens in human tumors. Semin Cancer Biol. 2012;22:350–58.

    Article  Google Scholar 

  35. Shi C, Zhu Y, Su Y, Chung LWK, Cheng T. β2-Microglobulin: emerging as a promising cancer therapeutic target. Drug Discov Today. 2009;14(1/2):25–30.

  36. Rowley DR et al. b-2 microglobulin is mitogenic to PC-3 prostatic carcinoma cells and antagonistic to transforming growth factor b1 action. Cancer Res. 1995;55:781–6.

    CAS  PubMed  Google Scholar 

  37. Huang WC et al. Beta2-microglobulin is a signaling and growth-promoting factor for human prostate cancer bone metastasis. Cancer Res. 2006;66:9108–16.

    Article  CAS  PubMed  Google Scholar 

  38. Nomura T et al. Beta2-microglobulin promotes the growth of human renal cell carcinoma through the activation of the protein kinase A, cyclic AMPresponsive element-binding protein, and vascular endothelial growth factor axis. Clin Cancer Res. 2006;12:7294–05.

    Article  CAS  PubMed  Google Scholar 

  39. Mori M et al. Antitumor effect of b2-microglobulin in leukemic cell-bearing mice via apoptosis-inducing activity: activation of caspase-3 and nuclear factor-kB. Cancer Res. 2001;61:4414–17.

    CAS  PubMed  Google Scholar 

  40. Min R et al. b2-Microglobulin as a negative growth regulator of myeloma cells. Br J Haematol. 2002;118:495–05.

    Article  CAS  PubMed  Google Scholar 

  41. Gordon J et al. Beta2-microglobulin induces caspase-dependent apoptosis in the CCRF-HSB-2 human leukemia cell line independently of the caspase-3, -8 and -9 pathways but through increased reactive oxygen species. Int J Cancer. 2003;103:316–27.

    Article  CAS  PubMed  Google Scholar 

  42. Shahoo NC, Rao KVS, Natrajan K. CD80 expression is induced on activated B cell following stimulation by CD86. Scand J Immunol. 2002;55:577–84.

    Article  Google Scholar 

  43. Campillo JA, Martínez-Escribano JA, Muro M, Moya-Quiles R. HLA class I and class II frequencies in patients with cutaneous malignant melanoma from southeastern Spain: the role of HLA-C in disease prognosis. Immunogenetics. 2006;57(12):926–33.

    Article  CAS  PubMed  Google Scholar 

  44. Christianson GJ et al. β2-Microglobulin-deficient mice are protected from hyper-gammaglobulinemia and have defective antibody responses because of increased IgG catabolism. J Immunol. 1997;159:4781–92.

    CAS  PubMed  Google Scholar 

  45. Hoglund P et al. b2-Microglobulin-deficient NK cells show increased sensitivity to MHC class I-mediated inhibition, but self tolerance does not depend upon target cell expression of H-2Kb and Db heavy chains. Eur J Immunol. 1998;28:370–8.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We are thankful to Dr. S.S. Agarwal, IMS, BHU, Varanasi, for providing the flow cytometry facility for the analysis of receptors, Dr. S. C. Lakhotia, Department of Zoology, BHU, for immunofluorescence imaging. We are grateful to UGC, New Delhi for the student grants to PKG.

Conflict of interest

The authors report no conflict of interest. The authors alone are responsible for the content and writing of this paper.

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Authors and Affiliations

  1. Department of Zoology, Faculty of Science, Banaras Hindu University, Varanasi, 221005, UP, India

    Pramod Kumar Gautam & Arbind Acharya

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  1. Pramod Kumar Gautam
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  2. Arbind Acharya
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Correspondence to Arbind Acharya.

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Gautam, P.K., Acharya, A. Antigenic Hsp70–peptide upregulate altered cell surface MHC class I expression in TAMs and increases anti-tumor function in Dalton’s lymphoma bearing mice. Tumor Biol. 36, 2023–2032 (2015). https://doi.org/10.1007/s13277-014-2809-9

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  • DOI: https://doi.org/10.1007/s13277-014-2809-9

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