Prognostic implications of type and density of tumour-infiltrating lymphocytes in gastric cancer

H E Lee, S W Chae, Y J Lee, M A Kim, H S Lee, B L Lee, W H Kim, H E Lee, S W Chae, Y J Lee, M A Kim, H S Lee, B L Lee, W H Kim

Abstract

The study aims to determine whether type and density of tumour-infiltrating lymphocytes (TILs) can predict the clinical course in gastric cancer. Gastric carcinomas (n=220) were immunostained for CD3, CD8, CD20, and CD45RO and evaluated for clinicopathologic characteristics. Number of TILs that immunostained positively for each marker were counted using NIH ImageJ software. Tumours were grouped into low- and high-density groups for each marker (CD3, CD8, CD45RO). The densities of CD3(+), CD8(+), and CD45RO(+) TILs were found to be independent predictors of lymph node metastasis by multivariate analysis with odds ratios (95% CI) of 0.425 (0.204-0.885), 0.325 (0.150-0.707), and 0.402 (0.190-0.850), respectively. Kaplan-Meier survival analysis revealed that patients in the high-density groups for CD3, CD8, and C45RO had a significantly longer survival time than the patients in the corresponding low-density groups, respectively. In multivariate survival analysis, the densities of CD3(+), CD8(+), and CD45RO(+) TILs remained independent prognostic factors with hazard ratios (95% CI) of 0.549 (0.317-0.951), 0.574 (0.347-0.949), and 0.507 (0.298-0.862), respectively. In conclusion, density of TILs was found to be independently predictive of regional lymph node metastasis and patient survival in gastric cancer.

Figures

Figure 1
Figure 1
Types of tumour-infiltrating lymphocytes. CD3 (A), CD8 (B), CD45RO (C), and CD20 (D) expressing cells were detected immunohistochemically. They are tumour-infiltrating total T cells, cytotoxic T cells, memory T cells, and B cells, respectively (original magnification, × 100).
Figure 2
Figure 2
Kaplan–Meier survival plots for the 220 gastric cancer patients as a function of TIL density. (A) Significant differences in overall survival were found between the low- and high-density groups of CD3, CD8, and CD45RO, by the log-rank tests. (B, C) Survival differences were consistently found when analysing with diverse combined TIL variables (refer to Table 1).
Figure 3
Figure 3
Kaplan–Meier survival analysis of TIL densities at different stages of the TNM classification (log-rank tests). High TIL density tended to be associated with longer overall survival within a given TNM stage. The results were from 75th percentile cutoffs.

References

    1. Chen CN, Lin JJ, Chen JJ, Lee PH, Yang CY, Kuo ML, Chang KJ, Hsieh FJ (2005) Gene expression profile predicts patient survival of gastric cancer after surgical resection. J Clin Oncol 23: 7286–7295
    1. Clemente CG, Mihm Jr MC, Bufalino R, Zurrida S, Collini P, Cascinelli N (1996) Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77: 1303–1310
    1. Coombes RC, Schein PS, Chilvers CE, Wils J, Beretta G, Bliss JM, Rutten A, Amadori D, Cortes-Funes H, Villar-Grimalt A (1990) A randomized trial comparing adjuvant fluorouracil, doxorubicin, and mitomycin with no treatment in operable gastric cancer. International Collaborative Cancer Group. J Clin Oncol 8: 1362–1369
    1. de Visser KE, Eichten A, Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6: 24–37
    1. Dunn GP, Old LJ, Schreiber RD (2004) The three Es of cancer immunoediting. Annu Rev Immunol 22: 329–360
    1. Engstrom PF, Lavin PT, Douglass Jr HO, Brunner KW (1985) Postoperative adjuvant 5-fluorouracil plus methyl-CCNU therapy for gastric cancer patients. Eastern Cooperative Oncology Group Study (EST 3275). Cancer 55: 1868–1873
    1. Fenoglio-Preiser C, Carneiro F, Correa P, Guilford P, Lambert R, Megraud F, Munoz N, Powell SM, Rugge M, Sasako M, Stolte M, Watanabe H (2000) Gastric carcinoma, In World Health Organization Classification of Tumors; Pathology and Genetics of Tumors of the Digestive System, Hamilton SR, Aaltonen LA (eds), pp 37–52. IARC Press: Lyon, France
    1. Fukuda K, Tsujitani S, Maeta Y, Yamaguchi K, Ikeguchi M, Kaibara N (2002) The expression of RCAS1 and tumor infiltrating lymphocytes in patients with T3 gastric carcinoma. Gastric Cancer 5: 220–227
    1. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313: 1960–1964
    1. 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: 2586–2593
    1. Goseki N, Takizawa T, Koike M (1992) Differences in the mode of the extension of gastric cancer classified by histological type: new histological classification of gastric carcinoma. Gut 33: 606–612
    1. Hippo Y, Taniguchi H, Tsutsumi S, Machida N, Chong JM, Fukayama M, Kodama T, Aburatani H (2002) Global gene expression analysis of gastric cancer by oligonucleotide microarrays. Cancer Res 62: 233–240
    1. Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, Fujii H (2003) Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clin Cancer Res 9: 4404–4408
    1. Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Che X, Iwashige H, Aridome K, Hokita S, Aikou T (2000) Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 88: 577–583
    1. Lauren P (1965) The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. an attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 64: 31–49
    1. Lee HS, Lee HK, Kim HS, Yang HK, Kim YI, Kim WH (2001) MUC1, MUC2, MUC5AC, and MUC6 expressions in gastric carcinomas: their roles as prognostic indicators. Cancer 92: 1427–1434
    1. Lewin KJ, Appleman HD (1996) Carcinoma of the stomach. In Atlas of Tumor Pathology; Tumors of the Esophagus and Stomach, Rosai J (ed), pp 245–330. Armed Forces Institute of Pathology: Washington DC, WA
    1. Maehara Y, Tomisaki S, Oda S, Kakeji Y, Tsujitani S, Ichiyoshi Y, Akazawa K, Sugimachi K (1997) Lymph node metastasis and relation to tumor growth potential and local immune response in advanced gastric cancer. Int J Cancer 74: 224–228
    1. Mazumdar M, Smith A, Bacik J (2003) Methods for categorizing a prognostic variable in a multivariable setting. Stat Med 28: 559–571
    1. Ming SC (1977) Gastric carcinoma. A pathobiological classification. Cancer 39: 2475–2485
    1. Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353: 2654–2666
    1. Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55: 74–108
    1. Piersma SJ, Jordanova ES, van Poelgeest MI, Kwappenberg KM, van der Hulst JM, Drijfhout JW, Melief CJ, Kenter GG, Fleuren GJ, Offringa R, van der Burg SH (2007) High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer. Cancer Res 67: 354–361
    1. Rosenberg SA, Yang JC, Restifo NP (2004) Cancer immunotherapy: moving beyond current vaccines. Nat Med 10: 909–915
    1. Sabbatini P, Odunsi K (2007) Immunologic approaches to ovarian cancer treatment. J Clin Oncol 25: 2884–2893
    1. Sharma P, Shen Y, Wen S, Yamada S, Jungbluth AA, Gnjatic S, Bajorin DF, Reuter VE, Herr H, Old LJ, Sato E (2007) CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc Natl Acad Sci USA 104: 3967–3972
    1. Taylor RC, Patel A, Panageas KS, Busam KJ, Brady MS (2007) Tumor-infiltrating lymphocytes predict sentinel lymph node positivity in patients with cutaneous melanoma. J Clin Oncol 25: 869–875
    1. Ueda Y, Fujimura T, Kinami S, Hirono Y, Yamaguchi A, Naitoh H, Tani T, Kaji M, Yamagishi H, Miwa K (2006) A randomized phase III trial of postoperative adjuvant therapy with S-1 alone versus S-1 plus PSK for stage II/IIIA gastric cancer: Hokuriku-Kinki Immunochemo-Therapy Study Group-Gastric Cancer (HKIT-GC). Jpn J Clin Oncol 36: 519–522
    1. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348: 203–213

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