Cancerous HLA class I expression and regulatory T cell infiltration in gastric cancer
Tóm tắt
Since antitumor immune reactions between tumors and intratumoral immunocytes have been verified in several human tumors, immunological therapeutic strategies must be considered to obtain the proper efficacy of tumor shrinkage under these conditions. Human leukocyte antigen (HLA) class I expression in cancer cells and degree of infiltration of regulatory T cells (Tregs) in the stroma have been regarded as important markers of antitumor immune reactions in the context of independent immunological mechanisms. In the current study, we investigated HLA class I expression and Treg cells infiltration in gastric cancer and discussed the clinical implications of this combinatory analysis in gastric cancer. A total of 141 gastric cancer patients who received R0 gastrectomy at Kagoshima University Hospital were studied. Immunohistochemically, in 141 gastric cancer patients, HLA class I expression and Treg cell infiltration in cancerous tissue were evaluated using HLA class I (EMR8-5) and forkhead box p3 (FOXP3) monoclonal antibodies. The correlation between clinical factors and tumor-infiltrating Treg cells was analyzed. HLA class I expression was positively associated with depth of tumor invasion (P < 0.05). Infiltration of Foxp3-positive cells did not correlate with any clinicopathological markers. HLA class I expression had no association with Treg cell infiltration (r = 0.04). A better postoperative outcome was associated with fewer numbers of Treg infiltration (P = 0.034). A combination of HLA and Treg analysis may lead to a more accurate prediction of postoperative outcome (P = 0.02). Two different antitumor immunological markers, Treg infiltration and HLA class I expression, affected clinicopathological factors in gastric cancer by different mechanisms. Thus, an immunological combination of HLA class I expression and Treg cell infiltration may more accurately predict postoperative outcome. Immunological balance needs to be restored after evaluation of each immunological deficit in gastric cancer.
Tài liệu tham khảo
Wong J, Jackson P (2011) Gastric cancer surgery: an American perspective on the current options and standards. Curr Treat Options Oncol 12:72–84
Tanizawa Y, Terashima M (2010) Lymph node dissection in the resection of gastric cancer: review of existing evidence. Gastric Cancer 13:137–148
Gotoda T, Iwasaki M, Kusano C, Seewald S, Oda I (2010) Endoscopic resection of early gastric cancer treated by guideline and expanded National Cancer Centre criteria. Br J Surg 97:868–871
Nomura S, Kaminishi M (2007) Surgical treatment of early gastric cancer. Dig Surg 24:96–100
Kobayashi M, Okabayashi T, Sano T, Araki K (2005) Metastatic bone cancer as a recurrence of early gastric cancer—characteristics and possible mechanisms. World J Gastroenterol 11:5587–5591
Bhutia SK, Mallick SK, Maiti TK (2010) Tumour escape mechanisms and their therapeutic implications in combination tumour therapy. Cell Biol Int 34:553–563
Kirkbride KC, Blobe GC (2003) Inhibiting the TGF-beta signalling pathway as a means of cancer immunotherapy. Expert Opin Biol Ther 3:251–261
Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Higashi H, Iwashige H, Aridome K, Hokita S, Aikou T (2002) CD3-zetachain expression of intratumoral lymphocytes is closely related to survival in gastric carcinoma patients. Cancer 94:1437–1442
Betts GJ, Clarke SL, Richards HE, Godkin AJ, Gallimore AM (2006) Regulating the immune response to tumours. Adv Drug Deliv Rev 58:948–961
Wang RF (2006) Regulatory T cells and innate immune regulation in tumor immunity. Springer Semin Immunopathol 28:17–23
Chang X, Zheng P, Liu Y (2006) FoxP3: a genetic link between immunodeficiency and autoimmune diseases. Autoimmun Rev 5:399–402
Curiel TJ, Coukos G, Zou L et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949
Gao Q, Qiu SJ, Fan J et al (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25:2586–2593
Griffiths RW, Elkord E, Gilham DE et al (2007) Frequency of regulatory T cells in renal cell carcinoma patients and investigation of correlation with survival. Cancer Immunol Immunother 56:1743–1753
Hiraoka N, Onozato K, Kosuge T, Hirohashi S (2006) Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 12:5423–5434
Ishigami S, Natsugoe S, Nakajo A, Arigami T, Kitazono M, Okumura H, Matsumoto M, Uchikado Y, Setoyama T, Sasaki K, Aikou T (2008) HLA-class I expression in gastric cancer. J Surg Oncol 97:605–608
Menon AG, Morreau H, Tollenaar RA, Alphenaar E, Van Puijenbroek M, Putter H, Janssen-Van Rhijn CM, Van De Velde CJ, Fleuren GJ, Kuppen PJ (2002) Down-regulation of HLA-A expression correlates with a better prognosis in colorectal cancer patients. Lab Invest 82:1725–1733
Speetjens FM, de Bruin EC, Morreau H, Zeestraten EC, Putter H, van Krieken JH, van Buren MM, van Velzen M, Dekker-Ensink NG, van de Velde CJ, Kuppen PJ (2008) Clinical impact of HLA class I expression in rectal cancer. Cancer Immunol Immunother 57:601–609
Kaneko K, Ishigami S, Kijima Y, Funasako Y, Hirata M, Okumura H, Shinchi H, Koriyama C, Ueno S, Yoshinaka H, Natsugoe S (2011) Clinical implication of HLA class I expression in breast cancer. BMC Cancer 11:454
de Kruijf EM, van Nes JG, Sajet A, Tummers QR, Putter H, Osanto S, Speetjens FM, Smit VT, Liefers GJ, van de Velde CJ, Kuppen PJ (2010) The predictive value of HLA class I tumor cell expression and presence of intratumoral Tregs for chemotherapy in patients with early breast cancer. Clin Cancer Res 16:1272–1280
Japanese Gastric Cancer Association (1998) Japanese classification of gastric carcinoma—2nd English Edition. Gastric Cancer 1:10–24
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pagès F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795):1960–1964
Seliger B (2012) Novel insights into the molecular mechanisms of HLA class I abnormalities. Cancer Immunol Immunother 61:249–254
Aptsiauri N, Cabrera T, Mendez R, Garcia-Lora A, Ruiz-Cabello F, Garrido F (2007) Role of altered expression of HLA class I molecules in cancer progression. Adv Exp Med Biol 601:123–131
Kitamura H, Torigoe T, Honma I, Sato E, Asanuma H, Hirohashi Y, Sato N, Tsukamoto T (2006) Effect of human leukocyte antigen class I expression of tumor cells on outcome of intravesical instillation of bacillus calmette-guerin immunotherapy for bladder cancer. Clin Cancer Res 12:4641–4644
Mizukami Y, Kono K, Maruyama T, Watanabe M, Kawaguchi Y, Kamimura K, Fujii H (2008) Downregulation of HLA Class I molecules in the tumour is associated with a poor prognosis in patients with oesophageal squamous cell carcinoma. Br J Cancer 99:1462–1467
Gasparoto TH, de Souza Malaspina TS, Benevides L, de Melo EJ Jr, Costa MR, Damante JH, Ikoma MR, Garlet GP, Cavassani KA, da Silva JS, Campanelli AP (2010) Patients with oral squamous cell carcinoma are characterized by increased frequency of suppressive regulatory T cells in the blood and tumor microenvironment. Cancer Immunol Immunother 59:819–828
Yokokawa J, Cereda V, Remondo C, Gulley JL, Arlen PM, Schlom J, Tsang KY (2008) Enhanced functionality of CD4+ CD25(high)FoxP3+ regulatory T cells in the peripheral blood of patients with prostate cancer. Clin Cancer Res 14:1032–1040
Hillen F, Baeten CI, van de Winkel A, Creytens D, van der Schaft DW, Winnepenninckx V, Griffioen AW (2008) Leukocyte infiltration and tumor cell plasticity are parameters of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 57:97–106
van Dongen M, Savage ND, Jordanova ES, Briaire-de Bruijn IH, Walburg KV, Ottenhoff TH, Hogendoorn PC, van der Burg SH, Gelderblom H, van Hall T (2010) Anti-inflammatory M2 type macrophages characterize metastasized and tyrosine kinase inhibitor-treated gastrointestinal stromal tumors. Int J Cancer 127:899–909
Pölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, Sauerwald A, Keyver-Paik MD, Kübler K, Büttner R, Kuhn WC, Hernando JJ (2010) Foxp3(+) cell infiltration and granzyme B(+)/Foxp3(+) cell ratio are associated with outcome in neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother 59:909–919
Ono M, Tsuda H, Shimizu C, Yamamoto S, Shibata T, Yamamoto H, Hirata T, Yonemori K, Ando M, Tamura K, Katsumata N, Kinoshita T, Takiguchi Y, Tanzawa H, Fujiwara Y (2011) Tumor-infiltrating lymphocytes are correlated with response to neoadjuvant chemotherapy in triple-negative breast cancer. Breast Cancer Res Treat
Halama N, Michel S, Kloor M, Zoernig I, Benner A, Spille A, Pommerencke T, von Knebel DM, Folprecht G, Luber B, Feyen N, Martens UM, Beckhove P, Gnjatic S, Schirmacher P, Herpel E, Weitz J, Grabe N, Jaeger D (2011) Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Cancer Res 71:5670–5677
Coe D, Begom S, Addey C, White M, Dyson J, Chai JG (2010) Depletion of regulatory T cells by anti-GITR mAb as a novel mechanism for cancer immunotherapy. Cancer Immunol Immunother 59:1367–1377
Cohen AD, Schaer DA, Liu C, Li Y, Hirschhorn-Cymmerman D, Kim SC, Diab A, Rizzuto G, Duan F, Perales MA, Merghoub T, Houghton AN, Wolchok JD (2010) Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS ONE 5:e10436
Ferris RL, Hunt JL, Ferrone S (2005) Human leukocyte antigen (HLA) class I defects in head and neck cancer: molecular mechanisms and clinical significance. Immunol Res 33:113–133
Garrido F, Cabrera T, Aptsiauri N (2010) “Hard” and “soft” lesions underlying the HLA class I alterations in cancer cells: implications for immunotherapy. Int J Cancer 127:249–256