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 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 6/2016

Open Access 01-06-2016 | Original Article

Tumour infiltrating lymphocytes correlate with improved survival in patients with oesophageal adenocarcinoma

Authors: Fergus Noble, Toby Mellows, Leo H. McCormick Matthews, Adrian C. Bateman, Scott Harris, Timothy J. Underwood, James P. Byrne, Ian S. Bailey, Donna M. Sharland, Jamie J. Kelly, John N. Primrose, Surinder S. Sahota, Andrew R. Bateman, Gareth J. Thomas, Christian H. Ottensmeier

Published in: Cancer Immunology, Immunotherapy | Issue 6/2016

Login to get access

Abstract

Background

Oesophageal adenocarcinoma (OAC) is increasingly common in the west, and survival remains poor at 10–15 % at 5 years. Immune responses are increasingly implicated as a determining factor of tumour progression. The ability of lymphocytes to recognise tumour antigens provides a mechanism for a host immune attack against cancer providing a potential treatment strategy.

Materials and Methods

Tumour infiltrating lymphocytes (TILs: CD3+, CD4+, CD8+ and FOXp3+) were assessed by immunohistochemistry using tissue microarrays in a contemporary and homogeneous cohort of OAC patients (n = 128) undergoing curative treatment.

Results

Multivariate analysis identified three independent prognostic factors for improved cancer-specific survival (CSS): increased CD8+ TILs (p = 0.003), completeness of resection (p < 0.0001) and lower pathological N stage (p < 0.0001). Independent prognostic factors for favourable disease-free survival included surgery-only treatment (p = 0.015), completeness of resection (p = 0.001), increased CD8+ TILs (p < 0.0001) and reduced pathological N stage (p < 0.0001). Higher levels of TILs in the pathological specimen were associated with significant pathological response to neoadjuvant chemotherapy (NAC). On multivariate analysis increased levels of CD4+ (p = 0.017) and CD8+ TILs (p = 0.005) were associated with significant local tumour regression and lymph node downstaging, respectively.

Discussion

Our results establish an association of TILs and survival in OAC, as seen in other solid tumours, and identify particular TIL subsets that are present at higher levels in patients who responded to NAC compared to non-responders. These findings highlight potential therapeutic strategies in EAC based on utilising the host immunological response and highlight the immune responses biomarker potential.
Appendix
Available only for authorised users
Literature
1.
Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357(9255):539–545CrossRefPubMed
2.
3.
4.
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(5795):1960–1964CrossRefPubMed
5.
Cowie A, Noble F, Underwood T (2014) Strategies to improve outcomes in esophageal adenocarcinoma. Expert Rev Anticancer Ther 14(6):677–687CrossRefPubMed
6.
Lepage C, Rachet B, Jooste V, Faivre J, Coleman MP (2008) Continuing rapid increase in esophageal adenocarcinoma in England and Wales. Am J Gastroenterol 103(11):2694–2699CrossRefPubMed
7.
Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ, Participants MT (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355(1):11–20CrossRefPubMed
8.
Allum WH, Blazeby JM, Griffin SM, Cunningham D, Jankowski JA, Wong R, Association of Upper Gastrointestinal Surgeons of Great B, Ireland tBSoG, the British Association of Surgical O (2011) Guidelines for the management of oesophageal and gastric cancer. Gut 60(11):1449–1472CrossRefPubMed
9.
Boon T, Coulie PG, Van den Eynde B (1997) Tumor antigens recognized by T cells. Immunol Today 18(6):267–268CrossRefPubMed
10.
Mukai S, Kjaergaard J, Shu S, Plautz GE (1999) Infiltration of tumors by systemically transferred tumor-reactive T lymphocytes is required for antitumor efficacy. Cancer Res 59(20):5245–5249PubMed
11.
Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW (2011) The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer 105(1):93–103CrossRefPubMedPubMedCentral
12.
Dutta S, Crumley AB, Fullarton GM, Horgan PG, McMillan DC (2011) Comparison of the prognostic value of tumour- and patient-related factors in patients undergoing potentially curative resection of oesophageal cancer. World J Surg 35(8):1861–1866CrossRefPubMed
13.
Crumley AB, Going JJ, Hilmy M, Dutta S, Tannahill C, McKernan M, Edwards J, Stuart RC, McMillan DC (2011) Interrelationships between tumor proliferative activity, leucocyte and macrophage infiltration, systemic inflammatory response, and survival in patients selected for potentially curative resection for gastroesophageal cancer. Ann Surg Oncol 18(9):2604–2612CrossRefPubMed
14.
Schumacher K, Haensch W, Roefzaad C, Schlag PM (2001) Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas. Cancer Res 61(10):3932–3936PubMed
15.
Zingg U, Montani M, Frey DM, Dirnhofer S, Esterman AJ, Went P, Oertli D (2010) Tumour-infiltrating lymphocytes and survival in patients with adenocarcinoma of the oesophagus. Eur J Surg Oncol 36(7):670–677CrossRefPubMed
16.
Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry-Amar M, Petiot JF, Roussel A, Jacob JH, Segol P, Samama G et al (1994) Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer 73(11):2680–2686PubMed
17.
Noble F, Nolan L, Bateman AC, Byrne JP, Kelly JJ, Bailey IS, Sharland DM, Rees CN, Iveson TJ, Underwood TJ, Bateman AR (2013) Refining pathological evaluation of neoadjuvant therapy for adenocarcinoma of the esophagus. World J Gastroenterol 19(48):9282–9293CrossRefPubMedPubMedCentral
18.
Noble F, Hopkins J, Curtis N, Kelly JJ, Bailey IS, Byrne JP, Bateman AC, Bateman AR, Underwood TJ (2013) The role of systemic inflammatory and nutritional blood-borne markers in predicting response to neoadjuvant chemotherapy and survival in oesophagogastric cancer. Med Oncol 30(3):596CrossRefPubMed
19.
Sobin LH, Gospodarowicz MK, Wittekind Ch (eds) (2009) International Union Against Cancer (UICC): TNM classification of malignant tumours, 7th edn. Wiley-Blackwell, Oxford, UK
20.
Sagar PM, Johnston D, McMahon MJ, Dixon MF, Quirke P (1993) Significance of circumferential resection margin involvement after oesophagectomy for cancer. Br J Surg 80(11):1386–1388CrossRefPubMed
21.
Simpson JA, Al-Attar A, Watson NF, Scholefield JH, Ilyas M, Durrant LG (2010) Intratumoral T cell infiltration, MHC class I and STAT1 as biomarkers of good prognosis in colorectal cancer. Gut 59(7):926–933CrossRefPubMed
22.
Klintrup K, Makinen JM, Kauppila S, Vare PO, Melkko J, Tuominen H, Tuppurainen K, Makela J, Karttunen TJ, Makinen MJ (2005) Inflammation and prognosis in colorectal cancer. Eur J Cancer 41(17):2645–2654CrossRefPubMed
23.
Jamieson NB, Mohamed M, Oien KA, Foulis AK, Dickson EJ, Imrie CW, Carter CR, McKay CJ, McMillan DC (2012) The relationship between tumor inflammatory cell infiltrate and outcome in patients with pancreatic ductal adenocarcinoma. Ann Surg Oncol 19(11):3581–3590CrossRefPubMed
24.
Proctor MJ, Morrison DS, Talwar D, Balmer SM, Fletcher CD, O'Reilly DS, Foulis AK, Horgan PG, McMillan DC (2011) A comparison of inflammation-based prognostic scores in patients with cancer: a glasgow inflammation outcome study. Eur J Cancer 47(17):2633–2641CrossRefPubMed
25.
Ladoire S, Arnould L, Apetoh L, Coudert B, Martin F, Chauffert B, Fumoleau P, Ghiringhelli F (2008) Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating FOXp3+ regulatory T cells. Clin Cancer Res 14(8):2413–2420CrossRefPubMed
26.
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(17):5670–5677CrossRefPubMed
27.
Chan MS, Wang L, Felizola SJ, Ueno T, Toi M, Loo W, Chow LW, Suzuki T, Sasano H (2012) Changes of tumor infiltrating lymphocyte subtypes before and after neoadjuvant endocrine therapy in estrogen receptor-positive breast cancer patients–an immunohistochemical study of Cd8+ and FOXp3+ using double immunostaining with correlation to the pathobiological response of the patients. Int J Biol Markers 27(4):e295–e304CrossRefPubMed
28.
Bracci L, Schiavoni G, Sistigu A, Belardelli F (2014) Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ 21(1):15–25CrossRefPubMedPubMedCentral
29.
Andersen MH, Sorensen RB, Schrama D, Svane IM, Becker JC, Thor Straten P (2008) Cancer treatment: the combination of vaccination with other therapies. Cancer Immunol Immunother 57(11):1735–1743CrossRefPubMedPubMedCentral
30.
Fareed KR, Ilyas M, Kaye PV, Soomro IN, Lobo DN, Parsons SL, Madhusudan S (2009) Tumour regression grade (TRG) analyses in patients with resectable gastro-oesophageal adenocarcinomas treated with platinum-based neoadjuvant chemotherapy. Histopathology 55(4):399–406CrossRefPubMed
31.
Ademuyiwa FO, Bshara W, Attwood K, Morrison C, Edge SB, Karpf AR, James SA, Ambrosone CB, O'Connor TL, Levine EG, Miliotto A, Ritter E, Ritter G, Gnjatic S, Odunsi K (2012) NY-ESO-1 cancer testis antigen demonstrates high immunogenicity in triple negative breast cancer. PLoS One 7(6):e38783CrossRefPubMedPubMedCentral
32.
Loi SMS, Salgado R, Sirtaine N, Jose V, Fumagalli D, Kellokumpu-Lehtinen PL, Bono P, Kataja V, Desmedt C, Piccart MJ, Loibl S, Denkert C, Smyth MJ, Joensuu H, Sotiriou C (2014) Tumor infiltrating lymphocytes is prognostic and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol 25(8):1544–1550CrossRefPubMed
33.
Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang YK, To GATI (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376(9742):687–697CrossRefPubMed
34.
Tamura K, Shimizu C, Hojo T, Akashi-Tanaka S, Kinoshita T, Yonemori K, Kouno T, Katsumata N, Ando M, Aogi K, Koizumi F, Nishio K, Fujiwara Y (2011) FcgammaR2A and 3A polymorphisms predict clinical outcome of trastuzumab in both neoadjuvant and metastatic settings in patients with HER2-positive breast cancer. Ann Oncol 22(6):1302–1307CrossRefPubMed
35.
Lissoni P, Brivio F, Fumagalli L, Messina G, Ghezzi V, Frontini L, Giani L, Vaghi M, Ardizzoia A, Gardani GS (2004) Efficacy of cancer chemotherapy in relation to the pretreatment number of lymphocytes in patients with metastatic solid tumors. Int J Biol Markers 19(2):135–140PubMed
36.
Gao Y, Zhou S, Jiang W, Huang M, Dai X (2003) Effects of ganopoly (a Ganoderma lucidum polysaccharide extract) on the immune functions in advanced-stage cancer patients. Immunol Invest 32(3):201–215CrossRefPubMed
37.
Chandler I, Houlston R, Landberg G (2011) A practical guide to constructing and using tissue microarrays. Methods Mol Biol 675:363–373CrossRefPubMed
38.
39.
Royston P, Altman DG, Sauerbrei W (2006) Dichotomizing continuous predictors in multiple regression: a bad idea. Stat Med 25(1):127–141CrossRefPubMed
40.
Ahmed SA, Talal N (1990) Sex hormones and the immune system Part 2 Animal data. Baillieres Clin Rheumatol 4(1):13–31CrossRefPubMed
41.
Ibrahim EM, Al-Foheidi ME, Al-Mansour MM, Kazkaz GA (2014) The prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancer: a meta-analysis. Breast Cancer Res Treat 148(3):467–476CrossRefPubMed
42.
Kim KJ, Lee KS, Cho HJ, Kim YH, Yang HK, Kim WH, Kang GH (2014) Prognostic implications of tumor-infiltrating FOXp3+ regulatory T cells and CD8+ cytotoxic T cells in microsatellite-unstable gastric cancers. Hum Pathol 45(2):285–293CrossRefPubMed
43.
Feichtenbeiner A, Haas M, Buttner M, Grabenbauer GG, Fietkau R, Distel LV (2014) Critical role of spatial interaction between CD8(+) and FOXp3(+) cells in human gastric cancer: the distance matters. Cancer Immunol Immunother 63(2):111–119CrossRefPubMed
44.
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(10):1849–1856CrossRefPubMed
Metadata
Title
Tumour infiltrating lymphocytes correlate with improved survival in patients with oesophageal adenocarcinoma
Authors
Fergus Noble
Toby Mellows
Leo H. McCormick Matthews
Adrian C. Bateman
Scott Harris
Timothy J. Underwood
James P. Byrne
Ian S. Bailey
Donna M. Sharland
Jamie J. Kelly
John N. Primrose
Surinder S. Sahota
Andrew R. Bateman
Gareth J. Thomas
Christian H. Ottensmeier
Publication date
01-06-2016
Publisher
Springer Berlin Heidelberg
Published in
Cancer Immunology, Immunotherapy / Issue 6/2016
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-016-1826-5

Other articles of this Issue 6/2016

Cancer Immunology, Immunotherapy 6/2016 Go to the issue

Original Article

Endostatin inhibits the growth and migration of 4T1 mouse breast cancer cells by skewing macrophage polarity toward the M1 phenotype

Original Article

Disease progression in recurrent glioblastoma patients treated with the VEGFR inhibitor axitinib is associated with increased regulatory T cell numbers and T cell exhaustion

Original Article

Myeloid-derived suppressor cells correlate with patient outcomes in hepatic arterial infusion chemotherapy for hepatocellular carcinoma

Review

Strategies to genetically engineer T cells for cancer immunotherapy

Original Article

Immunogenicity and efficacy of the novel cancer vaccine based on simian adenovirus and MVA vectors alone and in combination with PD-1 mAb in a mouse model of prostate cancer

Letter to the Editors

A case report of insulin-dependent diabetes as immune-related toxicity of pembrolizumab: presentation, management and outcome
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