Skip to main content
Erschienen in: Annals of Surgical Oncology 1/2015

01.01.2015 | Hepatobiliary Tumors

Low Infiltration of Peritumoral Regulatory T Cells Predicts Worse Outcome Following Resection of Colorectal Liver Metastases

verfasst von: Kazuya Nakagawa, MD, Kuniya Tanaka, MD, PhD, Yuki Homma, MD, PhD, Kazunori Nojiri, MD, PhD, Takafumi Kumamoto, MD, PhD, Kazuhisa Takeda, MD, PhD, Itaru Endo, MD, PhD

Erschienen in: Annals of Surgical Oncology | Ausgabe 1/2015

Einloggen, um Zugang zu erhalten

Abstract

Background

The tumor-infiltrating lymphocyte (TIL) count in several types of cancer, including colorectal cancer and colorectal liver metastases (CRLM), reportedly predicts survival following resection; however, the prognostic significance of the TIL counts remains controversial.

Methods

In total, 162 patients who underwent potentially curative resection for CRLM from 1992 to 2010 were immunohistochemically analyzed retrospectively. CD4, CD8, and FoxP3 were examined as markers for helper T cells, cytotoxic T cells, and regulatory T cells (Tregs), respectively. The correlation between patients’ TIL composition and long-term outcome was investigated.

Results

The median follow-up time was 46.6 months for all patients and 46.8 months for survivors. Cancer-specific survival (CSS) at 1, 3, and 5 years was 93.2, 65.6, and 51.0 %, respectively. The 5-year disease-free survival and CSS among patients with high infiltration of peritumoral Tregs was 44.2 and 74.8 %, respectively, while those of patients with low infiltration of peritumoral Tregs was 18.9 and 40.3 %, respectively (p < 0.01 for both). Multivariate analyses indicated that synchronous liver metastases, hypoalbuminemia, and low peritumoral Treg infiltration were significant predictors of unfavorable CSS.

Conclusions

Low peritumoral Treg infiltration proved to be a significant predictor of unfavorable CSS in patients undergoing resection for CRLM.
Literatur
1.
Zurück zum Zitat Howe HL, Wu X, Ries LA, et al. Annual report to the nation on the status of cancer, 1975–2003, featuring cancer among U.S. Hispanic/Latino populations. Cancer. 2006;107:1711–42.PubMedCrossRef Howe HL, Wu X, Ries LA, et al. Annual report to the nation on the status of cancer, 1975–2003, featuring cancer among U.S. Hispanic/Latino populations. Cancer. 2006;107:1711–42.PubMedCrossRef
2.
Zurück zum Zitat Rudy DR, Zdon MJ. Update on colorectal cancer. Am Fam Physician. 2000;61:1759–70, 1773–74. Rudy DR, Zdon MJ. Update on colorectal cancer. Am Fam Physician. 2000;61:1759–70, 1773–74.
3.
Zurück zum Zitat Miller G, Biernacki P, Kemeny NE, et al. Outcomes after resection of synchronous or metachronous hepatic and pulmonary colorectal metastases. J Am Coll Surg. 2007;205:231–8.PubMedCrossRef Miller G, Biernacki P, Kemeny NE, et al. Outcomes after resection of synchronous or metachronous hepatic and pulmonary colorectal metastases. J Am Coll Surg. 2007;205:231–8.PubMedCrossRef
4.
Zurück zum Zitat Kawasaki S, Makuuchi M, Kakazu T, et al. Resection for multiple metastatic liver tumors after portal embolization. Surgery. 1994;115:674–7.PubMed Kawasaki S, Makuuchi M, Kakazu T, et al. Resection for multiple metastatic liver tumors after portal embolization. Surgery. 1994;115:674–7.PubMed
5.
Zurück zum Zitat Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg. 2004;240:644–57.PubMedCentralPubMedCrossRef Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg. 2004;240:644–57.PubMedCentralPubMedCrossRef
6.
Zurück zum Zitat Tanaka K, Shimada H, Ueda M, Matsuo K, Endo I, Togo S. Role of hepatectomy in treating multiple bilobar colorectal cancer metastases. Surgery. 2008;143:259–70.PubMedCrossRef Tanaka K, Shimada H, Ueda M, Matsuo K, Endo I, Togo S. Role of hepatectomy in treating multiple bilobar colorectal cancer metastases. Surgery. 2008;143:259–70.PubMedCrossRef
7.
Zurück zum Zitat de Haas RJ, Wicherts DA, Flores E, Azoulay D, Castaing D, Adam R. R1 resection by necessity for colorectal liver metastases: is it still a contraindication to surgery? Ann Surg. 2008;248:626–37.PubMed de Haas RJ, Wicherts DA, Flores E, Azoulay D, Castaing D, Adam R. R1 resection by necessity for colorectal liver metastases: is it still a contraindication to surgery? Ann Surg. 2008;248:626–37.PubMed
8.
Zurück zum Zitat Adam R, Wicherts DA, de Haas RJ, et al. Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol. 2009;27:1829–35.PubMedCrossRef Adam R, Wicherts DA, de Haas RJ, et al. Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol. 2009;27:1829–35.PubMedCrossRef
9.
Zurück zum Zitat Muratore A, Ribero D, Zimmitti G, Mellano A, Langella S, Capussotti L. Resection margin and recurrence-free survival after liver resection of colorectal metastases. Ann Surg Oncol. 2010;17:1324–9.PubMedCrossRef Muratore A, Ribero D, Zimmitti G, Mellano A, Langella S, Capussotti L. Resection margin and recurrence-free survival after liver resection of colorectal metastases. Ann Surg Oncol. 2010;17:1324–9.PubMedCrossRef
10.
Zurück zum Zitat Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4.PubMedCrossRef Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4.PubMedCrossRef
11.
Zurück zum Zitat Leffers N, Gooden MJ, de Jong RA, et al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother. 2009;58:449–59.PubMedCrossRef Leffers N, Gooden MJ, de Jong RA, et al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother. 2009;58:449–59.PubMedCrossRef
12.
Zurück zum Zitat Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8 + tumor-infiltrating lymphocytes and a high CD8 +/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA. 2005;102:18538–43.PubMedCentralPubMedCrossRef Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8 + tumor-infiltrating lymphocytes and a high CD8 +/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA. 2005;102:18538–43.PubMedCentralPubMedCrossRef
13.
Zurück zum Zitat Zhang YL, Li J, Mo HY, Qiu F, Zheng LM, Qian CN, et al. Different subsets of tumor infiltrating lymphocytes correlate with NPC progression in different ways. Mol Cancer. 2010;9:4.PubMedCentralPubMedCrossRef Zhang YL, Li J, Mo HY, Qiu F, Zheng LM, Qian CN, et al. Different subsets of tumor infiltrating lymphocytes correlate with NPC progression in different ways. Mol Cancer. 2010;9:4.PubMedCentralPubMedCrossRef
14.
Zurück zum Zitat Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942–9.PubMedCrossRef Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942–9.PubMedCrossRef
15.
Zurück zum Zitat Barnett B, Kryczek I, Cheng P, Zou W, Curiel TJ. Regulatory T cells in ovarian cancer: biology and therapeutic potential. Am J Reprod Immunol. 2005;54:369–77.PubMedCrossRef Barnett B, Kryczek I, Cheng P, Zou W, Curiel TJ. Regulatory T cells in ovarian cancer: biology and therapeutic potential. Am J Reprod Immunol. 2005;54:369–77.PubMedCrossRef
16.
Zurück zum Zitat Yu P, Fu YX. Tumor-infiltrating T lymphocytes: friends or foes? Lab Invest. 2006;86:231–45.PubMedCrossRef Yu P, Fu YX. Tumor-infiltrating T lymphocytes: friends or foes? Lab Invest. 2006;86:231–45.PubMedCrossRef
17.
Zurück zum Zitat Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer. 2011;105:93–103.PubMedCentralPubMedCrossRef Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer. 2011;105:93–103.PubMedCentralPubMedCrossRef
19.
Zurück zum Zitat Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6:295–307.PubMedCrossRef Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6:295–307.PubMedCrossRef
20.
Zurück zum Zitat Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057–61.PubMedCrossRef Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057–61.PubMedCrossRef
21.
Zurück zum Zitat deLeeuw RJ, Kost SE, Kakal JA, Nelson BH. The prognostic value of FoxP3 + tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clin Can Res. 2012;18:3022–9.CrossRef deLeeuw RJ, Kost SE, Kakal JA, Nelson BH. The prognostic value of FoxP3 + tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clin Can Res. 2012;18:3022–9.CrossRef
22.
Zurück zum Zitat Gao Q, Qiu SJ, Fan J, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007;25:2586–93.PubMedCrossRef Gao Q, Qiu SJ, Fan J, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007;25:2586–93.PubMedCrossRef
23.
Zurück zum Zitat Salama P, Phillips M, Grieu F, et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol. 2009;27:186–92.PubMedCrossRef Salama P, Phillips M, Grieu F, et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol. 2009;27:186–92.PubMedCrossRef
24.
Zurück zum Zitat Frey DM, Droeser RA, Viehl CT, et al. High frequency of tumor-infiltrating FOXP3(+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int J Cancer. 2010;126:2635–43.PubMed Frey DM, Droeser RA, Viehl CT, et al. High frequency of tumor-infiltrating FOXP3(+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int J Cancer. 2010;126:2635–43.PubMed
25.
Zurück zum Zitat Ladoire S, Martin F, Ghiringhelli F. Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother. 2011;60:909–18.PubMedCrossRef Ladoire S, Martin F, Ghiringhelli F. Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother. 2011;60:909–18.PubMedCrossRef
26.
Zurück zum Zitat Katz SC, Bamboat ZM, Maker AV, et al. Regulatory T cell infiltration predicts outcome following resection of colorectal cancer liver metastases. Ann Surg Oncol. 2013;20:946–55.PubMedCentralPubMedCrossRef Katz SC, Bamboat ZM, Maker AV, et al. Regulatory T cell infiltration predicts outcome following resection of colorectal cancer liver metastases. Ann Surg Oncol. 2013;20:946–55.PubMedCentralPubMedCrossRef
27.
Zurück zum Zitat Tanaka K, Matsuyama R, Takeda K, Matsuo K, Nagano Y, Endo I. Aggressive liver resection including major-vessel resection for colorectal liver metastases. World J Hepatol. 2009;1:79–89.PubMedCentralPubMedCrossRef Tanaka K, Matsuyama R, Takeda K, Matsuo K, Nagano Y, Endo I. Aggressive liver resection including major-vessel resection for colorectal liver metastases. World J Hepatol. 2009;1:79–89.PubMedCentralPubMedCrossRef
28.
Zurück zum Zitat Tanaka K, Hiroshima Y, Nakagawa K, et al. Two-stage hepatectomy with effective perioperative chemotherapy does not induce tumor growth or growth factor expression in liver metastases from colorectal cancer. Surgery. 2013;153:179–88.PubMedCrossRef Tanaka K, Hiroshima Y, Nakagawa K, et al. Two-stage hepatectomy with effective perioperative chemotherapy does not induce tumor growth or growth factor expression in liver metastases from colorectal cancer. Surgery. 2013;153:179–88.PubMedCrossRef
29.
Zurück zum Zitat Homma Y, Taniguchi K, Murakami T, et al. Immunological impact of neoadjuvant chemoradiotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma. Ann Surg Oncol. 2014;21:670–6.PubMedCrossRef Homma Y, Taniguchi K, Murakami T, et al. Immunological impact of neoadjuvant chemoradiotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma. Ann Surg Oncol. 2014;21:670–6.PubMedCrossRef
30.
Zurück zum Zitat Miller R, Siegmund D. Maximally selected Chi square statistics. Biometrics. 1982;38:1011–6.CrossRef Miller R, Siegmund D. Maximally selected Chi square statistics. Biometrics. 1982;38:1011–6.CrossRef
31.
Zurück zum Zitat Tsuchikawa T, Miyamoto M, Yamamura Y, Sjochinohe T, Hirano S, Kondo S. The immunological impact of neoadjuvant chemotherapy on the tumor microenvironment of esophageal squamous cell carcinoma. Ann Surg Oncol. 2012;19:1713–9.PubMedCrossRef Tsuchikawa T, Miyamoto M, Yamamura Y, Sjochinohe T, Hirano S, Kondo S. The immunological impact of neoadjuvant chemotherapy on the tumor microenvironment of esophageal squamous cell carcinoma. Ann Surg Oncol. 2012;19:1713–9.PubMedCrossRef
32.
Zurück zum Zitat Ladoire S, Arnould L, Apetoh L, et al. Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating Foxp3+ regulatory T cells. Clin Can Res. 2008;14:2413–20.CrossRef Ladoire S, Arnould L, Apetoh L, et al. Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating Foxp3+ regulatory T cells. Clin Can Res. 2008;14:2413–20.CrossRef
33.
Zurück zum Zitat Shurin GV, Tourkova IL, Kaneno R, Shurin MR. Chemotherapeutic agents in noncytotoxic concentrations increase antigen presentation by dendritic cells via an IL-12-dependent mechanism. J Immunol. 2009;183:137–44.PubMedCentralPubMedCrossRef Shurin GV, Tourkova IL, Kaneno R, Shurin MR. Chemotherapeutic agents in noncytotoxic concentrations increase antigen presentation by dendritic cells via an IL-12-dependent mechanism. J Immunol. 2009;183:137–44.PubMedCentralPubMedCrossRef
34.
Zurück zum Zitat Erdman SE, Poutahidis T, Tomczak M, et al. CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice. Am J Pathol. 2003;162:691–702.PubMedCentralPubMedCrossRef Erdman SE, Poutahidis T, Tomczak M, et al. CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice. Am J Pathol. 2003;162:691–702.PubMedCentralPubMedCrossRef
35.
Zurück zum Zitat Erdman SE, Sohn JJ, Rao VP, Nambiar PR, Ge Z, Fox JG, et al. CD4+ CD25+ regulatory lymphocytes induce regression of intestinal tumors in ApcMin/+mice. Cancer Res. 2005;65:3998–4004.PubMedCrossRef Erdman SE, Sohn JJ, Rao VP, Nambiar PR, Ge Z, Fox JG, et al. CD4+ CD25+ regulatory lymphocytes induce regression of intestinal tumors in ApcMin/+mice. Cancer Res. 2005;65:3998–4004.PubMedCrossRef
36.
Zurück zum Zitat Gallimore AM, Simon AK. Positive and negative influences of regulatory T cells on tumour immunity. Oncogene. 2008;27:5886–93.PubMedCrossRef Gallimore AM, Simon AK. Positive and negative influences of regulatory T cells on tumour immunity. Oncogene. 2008;27:5886–93.PubMedCrossRef
37.
Zurück zum Zitat Allan SE, Crome SQ, Crellin NK, et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol. 2007;19:345–54.PubMedCrossRef Allan SE, Crome SQ, Crellin NK, et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol. 2007;19:345–54.PubMedCrossRef
38.
Zurück zum Zitat Morgan ME, van Bilsen JH, Bakker AM, et al. Expression of FOXP3 mRNA is not confined to CD4+ CD25+ T regulatory cells in humans. Hum Immunol. 2005;66:13–20.PubMedCrossRef Morgan ME, van Bilsen JH, Bakker AM, et al. Expression of FOXP3 mRNA is not confined to CD4+ CD25+ T regulatory cells in humans. Hum Immunol. 2005;66:13–20.PubMedCrossRef
Metadaten
Titel
Low Infiltration of Peritumoral Regulatory T Cells Predicts Worse Outcome Following Resection of Colorectal Liver Metastases
verfasst von
Kazuya Nakagawa, MD
Kuniya Tanaka, MD, PhD
Yuki Homma, MD, PhD
Kazunori Nojiri, MD, PhD
Takafumi Kumamoto, MD, PhD
Kazuhisa Takeda, MD, PhD
Itaru Endo, MD, PhD
Publikationsdatum
01.01.2015
Verlag
Springer US
Erschienen in
Annals of Surgical Oncology / Ausgabe 1/2015
Print ISSN: 1068-9265
Elektronische ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-014-3974-1

Weitere Artikel der Ausgabe 1/2015

Annals of Surgical Oncology 1/2015 Zur Ausgabe

Vorsicht, erhöhte Blutungsgefahr nach PCI!

10.05.2024 Koronare Herzerkrankung Nachrichten

Nach PCI besteht ein erhöhtes Blutungsrisiko, wenn die Behandelten eine verminderte linksventrikuläre Ejektionsfraktion aufweisen. Das Risiko ist umso höher, je stärker die Pumpfunktion eingeschränkt ist.

Darf man die Behandlung eines Neonazis ablehnen?

08.05.2024 Gesellschaft Nachrichten

In einer Leseranfrage in der Zeitschrift Journal of the American Academy of Dermatology möchte ein anonymer Dermatologe bzw. eine anonyme Dermatologin wissen, ob er oder sie einen Patienten behandeln muss, der eine rassistische Tätowierung trägt.

Deutlich weniger Infektionen: Wundprotektoren schützen!

08.05.2024 Postoperative Wundinfektion Nachrichten

Der Einsatz von Wundprotektoren bei offenen Eingriffen am unteren Gastrointestinaltrakt schützt vor Infektionen im Op.-Gebiet – und dient darüber hinaus der besseren Sicht. Das bestätigt mit großer Robustheit eine randomisierte Studie im Fachblatt JAMA Surgery.

Chirurginnen und Chirurgen sind stark suizidgefährdet

07.05.2024 Suizid Nachrichten

Der belastende Arbeitsalltag wirkt sich negativ auf die psychische Gesundheit der Angehörigen ärztlicher Berufsgruppen aus. Chirurginnen und Chirurgen bilden da keine Ausnahme, im Gegenteil.

Update Chirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

S3-Leitlinie „Diagnostik und Therapie des Karpaltunnelsyndroms“

Karpaltunnelsyndrom BDC Leitlinien Webinare
CME: 2 Punkte

Das Karpaltunnelsyndrom ist die häufigste Kompressionsneuropathie peripherer Nerven. Obwohl die Anamnese mit dem nächtlichen Einschlafen der Hand (Brachialgia parästhetica nocturna) sehr typisch ist, ist eine klinisch-neurologische Untersuchung und Elektroneurografie in manchen Fällen auch eine Neurosonografie erforderlich. Im Anfangsstadium sind konservative Maßnahmen (Handgelenksschiene, Ergotherapie) empfehlenswert. Bei nicht Ansprechen der konservativen Therapie oder Auftreten von neurologischen Ausfällen ist eine Dekompression des N. medianus am Karpaltunnel indiziert.

Prof. Dr. med. Gregor Antoniadis
Berufsverband der Deutschen Chirurgie e.V.

S2e-Leitlinie „Distale Radiusfraktur“

Radiusfraktur BDC Leitlinien Webinare
CME: 2 Punkte

Das Webinar beschäftigt sich mit Fragen und Antworten zu Diagnostik und Klassifikation sowie Möglichkeiten des Ausschlusses von Zusatzverletzungen. Die Referenten erläutern, welche Frakturen konservativ behandelt werden können und wie. Das Webinar beantwortet die Frage nach aktuellen operativen Therapiekonzepten: Welcher Zugang, welches Osteosynthesematerial? Auf was muss bei der Nachbehandlung der distalen Radiusfraktur geachtet werden?

PD Dr. med. Oliver Pieske
Dr. med. Benjamin Meyknecht
Berufsverband der Deutschen Chirurgie e.V.

S1-Leitlinie „Empfehlungen zur Therapie der akuten Appendizitis bei Erwachsenen“

Appendizitis BDC Leitlinien Webinare
CME: 2 Punkte

Inhalte des Webinars zur S1-Leitlinie „Empfehlungen zur Therapie der akuten Appendizitis bei Erwachsenen“ sind die Darstellung des Projektes und des Erstellungswegs zur S1-Leitlinie, die Erläuterung der klinischen Relevanz der Klassifikation EAES 2015, die wissenschaftliche Begründung der wichtigsten Empfehlungen und die Darstellung stadiengerechter Therapieoptionen.

Dr. med. Mihailo Andric
Berufsverband der Deutschen Chirurgie e.V.