CD8+ T cells; Immunosuppression; Peripheral lymphocytes; Small cell lung cancer; Antigens, CD; Biomarkers, Tumor; Adult; Aged; Aged, 80 and over; Antigens, CD/metabolism; Biomarkers, Tumor/blood; CD8-Positive T-Lymphocytes/immunology; Case-Control Studies; Cell Proliferation; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms/blood; Lung Neoplasms/immunology; Lung Neoplasms/pathology; Lymphocyte Subsets/immunology; Male; Middle Aged; Multivariate Analysis; Neoplasm Staging; Prognosis; Small Cell Lung Carcinoma/blood; Small Cell Lung Carcinoma/immunology; Small Cell Lung Carcinoma/pathology; Young Adult; Cell Movement; CD8-Positive T-Lymphocytes; Lung Neoplasms; Lymphocyte Subsets; Small Cell Lung Carcinoma; Biochemistry, Genetics and Molecular Biology (all); General Biochemistry, Genetics and Molecular Biology; General Medicine
Abstract :
[en] BACKGROUND: Immunosuppression caused by tumorigenesis may promote tumor progress and invasion. Here, we investigated whether the characteristics of circulating T lymphocyte subtypes in patients with extensive small cell lung cancer (ED-SCLC) can be used as an alternative marker of tumor progression.
METHODS: This study included 36 newly diagnosed ED-SCLC patients before treatment and the patients were followed up. 22 age and sex-matched healthy volunteers were selected as control. The percentages and proliferation potential of T lymphocyte subpopulations from peripheral blood were measured.
RESULTS: CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) were elevated in ED-SCLC patients compared with healthy controls (p = 0.0083). In contrast, the percentages of CD3+ and CD3+CD4+ T cells were significantly lower in SCLC patients (p < 0.001; p = 0.0014). The proliferation (%divided) of CD8+ T cells of SCLC patients was suppressed compared with healthy controls (p = 0.0058), but not of CD4+ T cells (p = 0.1611). Multivariate analyses showed that the %divided of CD8+ T cells is an independent predictor for PFS (HR: 4.342, 95% CI 1.324-14.245; p = 0.015). The percentages of peripheral Tregs and the degree of chemotherapy or radiotherapy induced lymphopenia negatively correlated with the proliferation of CD8+ T cells (p = 0.0225, r = - 0.379; p = 0.0003, r = - 0.464).
CONCLUSION: The present study indicates that SCLC patients have impaired immunity in peripheral blood, and the proliferation potential of circulating CD8+ T cells is a significant predicator for PFS.
Disciplines :
Oncology
Author, co-author :
An, Ning ; Université de Liège - ULiège > GIGA > GIGA Stem Cells - Cancer Signaling ; Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, China
Wang, Haoyi; Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
Jia, Wenxiao; Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
Jing, Wang; Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
Liu, Chao; Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
Zhu, Hui; Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. drzhuh@126.com
Yu, Jinming; Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, China. sdyujingming@163.com ; Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. sdyujingming@163.com
Language :
English
Title :
The prognostic role of circulating CD8+ T cell proliferation in patients with untreated extensive stage small cell lung cancer.
Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367-80.
Rudin CM, Ismaila N, Hann CL, Malhotra N, Movsas B, Norris K, et al. Treatment of small-cell lung cancer: American Society of Clinical Oncology Endorsement of the American College of Chest Physicians Guideline. J Clin Oncol. 2015;33:4106-11.
Travis WD. Update on small cell carcinoma and its differentiation from squamous cell carcinoma and other non-small cell carcinomas. Modern Pathol. 2012;25(1):S18-30.
Simon GR, Turrisi A. Management of small cell lung cancer: ACCP evidence-based clinical practice guidelines. Chest. 2007;132(3):324S-39S.
Byers LA, Rudin CM. Small cell lung cancer: where do we go from here? Cancer. 2015;121(5):664-72.
Puglisi M, Dolly S, Faria A, Myerson JS, Popat S, O'Brien ME. Treatment options for small cell lung cancer - do we have more choice? Br J Cancer. 2010;102(4):629-38.
Spigel DR, Socinski MA. Rationale for chemotherapy, immunotherapy, and checkpoint blockade in SCLC: beyond traditional treatment approaches. J Thor Oncol. 2013;8(5):587-98.
Darnell RB, DeAngelis LM. Regression of small-cell lung carcinoma in patients with paraneoplastic neuronal antibodies. Lancet (London, England). 1993;341(8836):21-2.
Nakamura H, Saji H, Ogata A, Hosaka M, Hagiwara M, Kawasaki N, et al. Immunologic parameters as significant prognostic factors in lung cancer. Lung Cancer. 2002;37(2):161-9.
Wang W, Hodkinson P, McLaren F, MacKinnon A, Wallace W, Howie S, et al. Small cell lung cancer tumour cells induce regulatory T lymphocytes, and patient survival correlates negatively with FOXP3+ cells in tumour infiltrate. Int J Cancer. 2012;131(6):E928-37.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74.
Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329-60.
Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27(4):450-61.
Topalian SL, Taube JM, Anders RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 2016;16(5):275.
Gallimore A, Glithero A, Godkin A, Tissot AC, Plückthun A, Elliott T, et al. Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J Exp Med. 1998;187(9):1383-93.
Lee PP, Yee C, Savage PA, Fong L, Brockstedt D, Weber JS, et al. Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat Med. 1999;5(6):677.
Kurachi M. CD8+ T cell exhaustion. Seminars in immunopathology. Berlin: Springer; 2019.
Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 2015;36(4):265-76.
Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439(7077):682.
Gros A, Parkhurst MR, Tran E, Pasetto A, Robbins PF, Ilyas S, et al. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat Med. 2016;22(4):433.
Tahara H, Ide K, Basnet N, Tanaka Y, Ohdan H. Determination of the precursor frequency and the reaction intensity of xenoreactive human T lymphocytes. Xenotransplantation. 2010;17(3):188-96.
Tanaka Y, Ohdan H, Onoe T, Asahara T. Multiparameter flow cytometric approach for simultaneous evaluation of proliferation and cytokine-secreting activity in T cells responding to allo-stimulation. Immunol Invest. 2004;33(3):309-24.
Lau KM, Cheng SH, Lo KW, Lee SAKW, Woo JKS, van Hasselt CA, et al. Increase in circulating Foxp3+CD4+CD25high regulatory T cells in nasopharyngeal carcinoma patients. Br J Cancer. 2007;96:617.
Hu X, Gu Y, Zhao S, Hua S, Jiang Y. Elevated circulating CD4(+)CD25(-)Foxp3(+) regulatory T cells in patients with nonsmall cell lung cancer. Cancer Biother Radiopharm. 2019;34:325-33.
Tiwari M. From tumor immunology to cancer immunotherapy: miles to go. J Cancer Res Ther. 2010;6:427-31.
Kinoshita T, Muramatsu R, Fujita T, Nagumo H, Sakurai T, Noji S, et al. Prognostic value of tumor-infiltrating lymphocytes differs depending on histological type and smoking habit in completely resected non-small-cell lung cancer. Ann Oncol. 2016;27(11):2117-23.
Marshall EA, Ng KW, Kung SH, Conway EM, Martinez VD, Halvorsen EC, et al. Emerging roles of T helper 17 and regulatory T cells in lung cancer progression and metastasis. Mol Cancer. 2016;15(1):67.
Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B, et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007;132(7):2328-39.
Holcombe RF, Jacobson J, Dakhil SR, Stewart RM, Betzing KS, Kannan K, et al. Association of immune parameters with clinical outcome in stage III colon cancer: results of Southwest Oncology Group Protocol 9009. Cancer Immunol Immunother. 1999;48(9):533-9.
Vesely P, Touskova M, Melichar B. Phenotype of peripheral blood leukocytes and survival of patients with metastatic colorectal cancer. Int J Biol Markers. 2005;20(2):126-33.
Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, et al. Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 2001;61(12):4766-72.
Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005;6(4):345-52.
Chen W, Jin W, Hardegen N, Lei K-J, Li L, Marinos N, et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J Exp Med. 2003;198(12):1875-86.
Okita R, Saeki T, Takashima S, Yamaguchi Y, Toge T. CD4+CD25+ regulatory T cells in the peripheral blood of patients with breast cancer and non-small cell lung cancer. Oncol Rep. 2005;14(5):1269-73.
Kaech SM, Cui W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol. 2012;12(11):749.
Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15(8):486.
Wang HY, Wang RF. Regulatory T cells and cancer. Curr Opin Immunol. 2007;19(2):217-23.
Chowdhary M, Switchenko JM, Press RH, Jhaveri J, Buchwald ZS, Blumenfeld PA, et al. Post-treatment neutrophil-to-lymphocyte ratio predicts for overall survival in brain metastases treated with stereotactic radiosurgery. J Neurooncol. 2018;139(3):689-97.
Onyema OO, Decoster L, Njemini R, Forti LN, Bautmans I, De Waele M, et al. Chemotherapy-induced changes and immunosenescence of CD8+ T-cells in patients with breast cancer. Anticancer Res. 2015;35(3):1481-9.
