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Published in: Breast Cancer 1/2017

Open Access 01-01-2017 | Original Article

Altered expression of major immune regulatory molecules in peripheral blood immune cells associated with breast cancer

Authors: Kosuke Kawaguchi, Eiji Suzuki, Ayane Yamaguchi, Michio Yamamoto, Satoshi Morita, Masakazu Toi

Published in: Breast Cancer | Issue 1/2017

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Abstract

Background

The purpose of this study was to clarify the alterations of major immune regulators in peripheral blood mononuclear cells (PBMCs) of cancer patients and to analyze the association with the disease progression in breast cancer patients.

Methods

The study included 6 healthy volunteers (HVs), 12 primary breast cancer (PBC) patients, and 30 metastatic breast cancer (MBC) patients. The expression of immune regulators such as, CCR6, CD4, CD8, CD14, CD40, CD56, CD80, CTLA4, CXCR4, FOXP3, IDO-1, IDO-2, NKG2D, NRP-1, PD-1, and PD-L1 mRNA in PBMCs was measured by quantitative RT-PCR. Analysis of variance with contrasts was performed to find expression patterns of the three groups (HVs, PBC, MBC).

Results

We clarified the alterations of mRNA of major immune regulators PD-L1, FOXP3, CD80, CD40, and CD14 in PBMCs of cancer patients and the association of these alternations with disease progression. Furthermore, PD-L1 expression was correlated with serum interferon-γ production.

Conclusion

Our data suggested that mRNA expressions of PD-L1, FOXP3, CD80, CD40 and CD14 in PBMCs are affected by disease progression. Understanding the roles of these various interactions will be of importance to future studies aiming to uncover biomarkers for predicting response to immune therapy.
Literature
1.
go back to reference Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–35.CrossRefPubMedPubMedCentral Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–35.CrossRefPubMedPubMedCentral
2.
go back to reference Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.CrossRefPubMedPubMedCentral Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.CrossRefPubMedPubMedCentral
3.
go back to reference Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.CrossRefPubMedPubMedCentral Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.CrossRefPubMedPubMedCentral
4.
go back to reference Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus Everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13.CrossRefPubMed Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus Everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13.CrossRefPubMed
5.
go back to reference Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122–33.CrossRefPubMed Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122–33.CrossRefPubMed
6.
go back to reference Campbell DE, Tustin NB, Riedel E, Tustin R 3rd, Taylor J, Murray J, et al. Cryopreservation decreases receptor PD-1 and ligand PD-L1 coinhibitory expression on peripheral blood mononuclear cell-derived T cells and monocytes. Clin Vaccine Immunol. 2009;16:1648–53.CrossRefPubMedPubMedCentral Campbell DE, Tustin NB, Riedel E, Tustin R 3rd, Taylor J, Murray J, et al. Cryopreservation decreases receptor PD-1 and ligand PD-L1 coinhibitory expression on peripheral blood mononuclear cell-derived T cells and monocytes. Clin Vaccine Immunol. 2009;16:1648–53.CrossRefPubMedPubMedCentral
7.
go back to reference Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.CrossRefPubMedPubMedCentral Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.CrossRefPubMedPubMedCentral
8.
go back to reference Brown SD, Warren RL, Gibb EA, Martin SD, Spinelli JJ, Nelson BH, et al. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res. 2014;24:743–50.CrossRefPubMedPubMedCentral Brown SD, Warren RL, Gibb EA, Martin SD, Spinelli JJ, Nelson BH, et al. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res. 2014;24:743–50.CrossRefPubMedPubMedCentral
9.
go back to reference Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160:48–61.CrossRefPubMedPubMedCentral Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160:48–61.CrossRefPubMedPubMedCentral
10.
go back to reference Rutledge WC, Kong J, Gao J, Gutman DA, Cooper LA, Appin C, et al. Tumor-infiltrating lymphocytes in glioblastoma are associated with specific genomic alterations and related to transcriptional class. Clin Cancer Res. 2013;19:4951–60.CrossRefPubMed Rutledge WC, Kong J, Gao J, Gutman DA, Cooper LA, Appin C, et al. Tumor-infiltrating lymphocytes in glioblastoma are associated with specific genomic alterations and related to transcriptional class. Clin Cancer Res. 2013;19:4951–60.CrossRefPubMed
11.
go back to reference Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563–7.CrossRefPubMedPubMedCentral Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563–7.CrossRefPubMedPubMedCentral
12.
go back to reference Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515:558–62.CrossRefPubMed Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515:558–62.CrossRefPubMed
13.
go back to reference Denkert C, von Minckwitz G, Brase JC, Sinn BV, Gade S, Kronenwett R, et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol. 2015;33:983–91.CrossRefPubMed Denkert C, von Minckwitz G, Brase JC, Sinn BV, Gade S, Kronenwett R, et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol. 2015;33:983–91.CrossRefPubMed
14.
go back to reference Graw S, Meier R, Minn K, Bloomer C, Godwin AK, Fridley B, et al. Robust gene expression and mutation analyses of RNA-sequencing of formalin-fixed diagnostic tumor samples. Sci Rep. 2015;5:12335.CrossRefPubMedPubMedCentral Graw S, Meier R, Minn K, Bloomer C, Godwin AK, Fridley B, et al. Robust gene expression and mutation analyses of RNA-sequencing of formalin-fixed diagnostic tumor samples. Sci Rep. 2015;5:12335.CrossRefPubMedPubMedCentral
15.
go back to reference Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203:883–95.CrossRefPubMedPubMedCentral Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203:883–95.CrossRefPubMedPubMedCentral
16.
go back to reference Myklebust JH, Irish JM, Brody J, Czerwinski DK, Houot R, Kohrt HE, et al. High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells. Blood. 2013;121:1367–76.CrossRefPubMedPubMedCentral Myklebust JH, Irish JM, Brody J, Czerwinski DK, Houot R, Kohrt HE, et al. High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells. Blood. 2013;121:1367–76.CrossRefPubMedPubMedCentral
17.
go back to reference Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy–inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580–7.CrossRefPubMed Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy–inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580–7.CrossRefPubMed
19.
go back to reference van Rooij N, van Buuren MM, Philips D, Velds A, Toebes M, Heemskerk B, et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol. 2013;31:e439–42.CrossRefPubMed van Rooij N, van Buuren MM, Philips D, Velds A, Toebes M, Heemskerk B, et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol. 2013;31:e439–42.CrossRefPubMed
20.
go back to reference Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10.CrossRefPubMed Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10.CrossRefPubMed
22.
go back to reference Grewal IS, Flavell RA. CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol. 1998;16:111–35.CrossRefPubMed Grewal IS, Flavell RA. CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol. 1998;16:111–35.CrossRefPubMed
23.
go back to reference Zippelius A, Schreiner J, Herzig P, Muller P. Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment. Cancer Immunol Res. 2015;3:236–44.CrossRefPubMed Zippelius A, Schreiner J, Herzig P, Muller P. Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment. Cancer Immunol Res. 2015;3:236–44.CrossRefPubMed
24.
go back to reference Peach RJ, Bajorath J, Naemura J, Leytze G, Greene J, Aruffo A, et al. Both extracellular immunoglobin-like domains of CD80 contain residues critical for binding T cell surface receptors CTLA-4 and CD28. J Biol Chem. 1995;270:21181–7.CrossRefPubMed Peach RJ, Bajorath J, Naemura J, Leytze G, Greene J, Aruffo A, et al. Both extracellular immunoglobin-like domains of CD80 contain residues critical for binding T cell surface receptors CTLA-4 and CD28. J Biol Chem. 1995;270:21181–7.CrossRefPubMed
25.
go back to reference Walker LS, Sansom DM. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol. 2011;11:852–63.CrossRefPubMed Walker LS, Sansom DM. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol. 2011;11:852–63.CrossRefPubMed
26.
go back to reference Lenschow DJ, Zeng Y, Thistlethwaite JR, Montag A, Brady W, Gibson MG, et al. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science. 1992;257:789–92.CrossRefPubMed Lenschow DJ, Zeng Y, Thistlethwaite JR, Montag A, Brady W, Gibson MG, et al. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science. 1992;257:789–92.CrossRefPubMed
27.
go back to reference Linsley PS, Wallace PM, Johnson J, Gibson MG, Greene JL, Ledbetter JA, et al. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science. 1992;257:792–5.CrossRefPubMed Linsley PS, Wallace PM, Johnson J, Gibson MG, Greene JL, Ledbetter JA, et al. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science. 1992;257:792–5.CrossRefPubMed
28.
go back to reference Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007;13:84–8.CrossRefPubMed Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007;13:84–8.CrossRefPubMed
29.
go back to reference Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med. 2013;5:200ra116.CrossRefPubMedPubMedCentral Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med. 2013;5:200ra116.CrossRefPubMedPubMedCentral
Metadata
Title
Altered expression of major immune regulatory molecules in peripheral blood immune cells associated with breast cancer
Authors
Kosuke Kawaguchi
Eiji Suzuki
Ayane Yamaguchi
Michio Yamamoto
Satoshi Morita
Masakazu Toi
Publication date
01-01-2017
Publisher
Springer Japan
Published in
Breast Cancer / Issue 1/2017
Print ISSN: 1340-6868
Electronic ISSN: 1880-4233
DOI
https://doi.org/10.1007/s12282-016-0682-7

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