Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 4/2014

01-04-2014 | Original Article

PD-1+ immune cell infiltration inversely correlates with survival of operable breast cancer patients

Authors: Shenyou Sun, Xiaochun Fei, Yan Mao, Xiumin Wang, David H. Garfield, Ou Huang, Jinglong Wang, Fei Yuan, Long Sun, Qixiang Yu, Xiaolong Jin, Jianhua Wang, Kunwei Shen

Published in: Cancer Immunology, Immunotherapy | Issue 4/2014

Login to get access

Abstract

The programmed death-1 (PD-1) molecule is mainly expressed on functionally “exhausted” CD8+ T cells, dampening the host antitumor immune response. We evaluated the ratio between effective and regulatory T cells (Tregs) and PD-1 expression as a prognostic factor for operable breast cancer patients. A series of 218 newly diagnosed invasive breast cancer patients who had undergone primary surgery at Ruijin Hospital were identified. The influence of CD8+ cytotoxic T lymphocytes, FOXP3+ (Treg cell marker), and PD-1+ immune cell counts on prognosis was analyzed utilizing immunohistochemistry. Both PD-1+ immune cells and FOXP3+ Tregs counts were significantly associated with unfavorable prognostic factors. In bivariate, but not multivariate analysis, high tumor infiltrating PD-1+ cell counts correlated with significantly shorter patient survival. Our results suggest a prognostic value of the PD-1+ immune cell population in such breast cancer patients. Targeting the PD-1 pathway may be a feasible approach to treating patients with breast cancer.
Appendix
Available only for authorised users
Literature
1.
Caras I, Grigorescu A, Stavaru C, Radu D, Mogos I, Szegli G, Salageanu A (2004) Evidence for immune defects in breast and lung cancer patients. Cancer Immunol Immunother 53:1146–1152PubMedCrossRef
2.
Andre F, Dieci MV, Dubsky P, Sotiriou C, Curigliano G, Denkert C, Loi S (2013) Molecular pathways: involvement of immune pathways in the therapeutic response and outcome in breast cancer. Clin Cancer Res 19:28–33PubMedCrossRef
3.
Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH, Ellis IO, Green AR (2011) Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol 29:1949–1955PubMedCrossRef
4.
Liu F, Lang R, Zhao J, Zhang X, Pringle GA, Fan Y, Yin D, Gu F, Yao Z, Fu L (2011) CD8(+) cytotoxic T cell and FOXP3(+) regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes. Breast Cancer Res Treat 130:645–655PubMedCrossRef
5.
6.
7.
Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565–1570PubMedCrossRef
8.
9.
deLeeuw RJ, Kost SE, Kakal JA, Nelson BH (2012) The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clin Cancer Res 18:3022–3029PubMedCrossRef
10.
Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264PubMedCrossRef
11.
12.
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800PubMedCrossRef
13.
Monaghan SF, Thakkar RK, Tran ML, Huang X, Cioffi WG, Ayala A, Heffernan DS (2012) Programmed death 1 expression as a marker for immune and physiological dysfunction in the critically ill surgical patient. Shock 38:117–122PubMedCrossRef
14.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454PubMedCentralPubMedCrossRef
15.
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465PubMedCentralPubMedCrossRef
16.
17.
Janakiram M, Abadi YM, Sparano JA, Zang X (2012) T cell coinhibition and immunotherapy in human breast cancer. Discov Med 14(77):229–236PubMed
18.
19.
Ghebeh H, Barhoush E, Tulbah A, Elkum N, Al-Tweigeri T, Dermime S (2008) FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: implication for immunotherapy. BMC Cancer 8:57PubMedCentralPubMedCrossRef
20.
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, Kwon ED (2007) PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res 13:1757–1761PubMedCrossRef
21.
Hensel JA, Flaig TW, Theodorescu D (2012) Clinical opportunities and challenges in targeting tumour dormancy. Nat Rev Clin Oncol 10:41–51PubMedCrossRef
22.
Elston C, Ellis I (2002) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 41(3A):154–161PubMedCrossRef
23.
Black M, Speer F, Opler S (1956) Structural representations of tumor-host relationships in mammary carcinoma; biologic and prognostic significance. Am J Clin Pathol 26:250PubMed
24.
25.
Stewart TJ, Smyth MJ (2011) Improving cancer immunotherapy by targeting tumor-induced immune suppression. Cancer Metastasis Rev 30:125–140PubMedCrossRef
26.
Fridman WH, Pages F, Sautes-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12:298–306PubMedCrossRef
27.
Ghebeh H, Mohammed S, Al-Omair A, Qattan A, Lehe C, Al-Qudaihi G, Elkum N, Alshabanah M, Bin Amer S, Tulbah A, Ajarim D, Al-Tweigeri T, Dermime S (2006) The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia 8:190–198PubMedCentralPubMedCrossRef
28.
Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen L (2012) Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 4:127–137CrossRef
29.
Rozali EN, Hato SV, Robinson BW, Lake RA, Lesterhuis WJ (2012) Programmed death ligand 2 in cancer-induced immune suppression. Clin Dev Immunol 2012:656340PubMedCentralPubMedCrossRef
30.
Hasan A, Ghebeh H, Lehe C, Ahmad R, Dermime S (2011) Therapeutic targeting of B7-H1 in breast cancer. Expert Opin Ther Targets 15:1211–1225PubMedCrossRef
31.
Poschke I, De Boniface J, Mao Y, Kiessling R (2012) Tumor-induced changes in the phenotype of blood-derived and tumor-associated T cells of early stage breast cancer patients. Int J Cancer 131(7):1611–1620PubMedCrossRef
32.
Chen DS, Irving BA, Hodi FS (2012) Molecular pathways: next-generation immunotherapy—inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res 18:6580–6587PubMedCrossRef
33.
Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH (2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206:3015–3029PubMedCentralPubMedCrossRef
34.
35.
Shi F, Shi M, Zeng Z, Qi RZ, Liu ZW, Zhang JY, Yang YP, Tien P, Wang FS (2011) PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int J Cancer 128:887–896PubMedCrossRef
36.
Wang SF, Fouquet S, Chapon M, Salmon H, Regnier F, Labroquère K, Badoual C, Damotte D, Validire P, Maubec E, Delongchamps NB, Cazes A, Gibault L, Garcette M, Dieu-Nosjean MC, Zerbib M, Avril MF, Prévost-Blondel A, Randriamampita C, Trautmann A, Bercovici N (2011) Early T cell signalling is reversibly altered in PD-1+ T lymphocytes infiltrating human tumors. PLoS One 6:e17621PubMedCentralPubMedCrossRef
37.
Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25:2586–2593PubMedCrossRef
38.
Muenst S, Soysal S, Gao F, Obermann E, Oertli D, Gillanders W (2013) The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat 139:667–676PubMedCrossRef
39.
Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, Honjo T, Fujii S (2007) Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA 104:3360–3365PubMedCentralPubMedCrossRef
40.
Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Lee AH, Ellis IO, Green AR (2011) An evaluation of the clinical significance of FOXP3+ infiltrating cells in human breast cancer. Breast Cancer Res Treat 127:99–108PubMedCrossRef
41.
Topfer K, Kempe S, Muller N, Schmitz M, Bachmann M, Cartellieri M, Schackert G, Temme A (2011) Tumor evasion from T cell surveillance. J Biomed Biotechnol 2011:918471PubMedCentralPubMedCrossRef
42.
Heys SD, Stewart KN, McKenzie EJ, Miller ID, Wong SY, Sellar G, Rees AJ (2012) Characterisation of tumour-infiltrating macrophages: impact on response and survival in patients receiving primary chemotherapy for breast cancer. Breast Cancer Res Treat 135:539–548PubMedCrossRef
43.
44.
Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, Banham AH (2006) Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 24:5373–5380PubMedCrossRef
45.
Liu H, Zhang T, Ye J, Li H, Huang J, Li X, Wu B, Huang X, Hou J (2012) Tumor-infiltrating lymphocytes predict response to chemotherapy in patients with advance non-small cell lung cancer. Cancer Immunol Immunother 61:1849–1856PubMedCrossRef
46.
West NR, Kost SE, Martin SD, Milne K, Deleeuw RJ, Nelson BH, Watson PH (2013) Tumour-infiltrating FOXP3(+) lymphocytes are associated with cytotoxic immune responses and good clinical outcome in oestrogen receptor-negative breast cancer. Br J Cancer 108:155–162PubMedCentralPubMedCrossRef
47.
Baker K, Lachapelle J, Zlobec I, Bismar TA, Terracciano L, Foulkes WD (2011) Prognostic significance of CD8+ T lymphocytes in breast cancer depends upon both oestrogen receptor status and histological grade. Histopathology 58:1107–1116PubMed
48.
Liu S, Lachapelle J, Leung S, Gao D, Foulkes WD, Nielsen TO (2012) CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Res 14:R48PubMedCentralPubMedCrossRef
49.
Mohd Sharial MS, Crown J, Hennessy BT (2012) Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer. Ann Oncol 23:3007–3016PubMedCentralPubMedCrossRef
50.
Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, Rosenberg SA (2009) Tumor antigen—specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114:1537–1544PubMedCentralPubMedCrossRef
51.
Zhou Q, Munger ME, Highfill SL, Tolar J, Weigel BJ, Riddle M, Sharpe AH, Vallera DA, Azuma M, Levine BL, June CH, Murphy WJ, Munn DH, Blazar BR (2010) Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia. Blood 116:2484–2493PubMedCentralPubMedCrossRef
52.
53.
Flemming A (2012) Cancer: PD1 makes waves in anticancer immunotherapy. Nat Rev Drug Discov 11:601–605PubMedCrossRef
54.
Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704PubMedCrossRef
Metadata
Title
PD-1+ immune cell infiltration inversely correlates with survival of operable breast cancer patients
Authors
Shenyou Sun
Xiaochun Fei
Yan Mao
Xiumin Wang
David H. Garfield
Ou Huang
Jinglong Wang
Fei Yuan
Long Sun
Qixiang Yu
Xiaolong Jin
Jianhua Wang
Kunwei Shen
Publication date
01-04-2014
Publisher
Springer Berlin Heidelberg
Published in
Cancer Immunology, Immunotherapy / Issue 4/2014
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-014-1519-x

Other articles of this Issue 4/2014

Cancer Immunology, Immunotherapy 4/2014 Go to the issue

Original Article

A combination trial of vaccine plus ipilimumab in metastatic castration-resistant prostate cancer patients: immune correlates

Original Article

Immunologic response to the survivin-derived multi-epitope vaccine EMD640744 in patients with advanced solid tumors

Original Article

Apoptotic blebs from leukemic cells as a preferred source of tumor-associated antigen for dendritic cell-based vaccines

Original Article

Concomitant gemcitabine therapy negatively affects DC vaccine-induced CD8+ T-cell and B-cell responses but improves clinical efficacy in a murine pancreatic carcinoma model

Original Article

Phosphorothioate-modified CpG oligodeoxynucleotide (CpG ODN) induces apoptosis of human hepatocellular carcinoma cells independent of TLR9

Original Article

Cryoimmunotherapy with local co-administration of ex vivo generated dendritic cells and CpG-ODN immune adjuvant, elicits a specific antitumor immunity
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits