Skip to main content

Advertisement

SpringerLink
Log in

T-Helper 1 Immune Response in Metastatic Lymph Nodes of Pancreatic Ductal Adenocarcinoma: A Marker For Prolonged Survival

  • Pancreatic Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Although lymph node (LN) metastases is considered a grave prognostic sign in pancreatic ductal adenocarcinoma (PDAC), patients with positive lymph nodes (PLN) constitute a heterogeneous group. Our purpose was to identify morphological and immune parameters in the primary tumor and in PLN of resected PDAC patients, which could further stratify these patients to different subgroups.

Methods

We retrospectively evaluated histological and immunohistochemical characteristics of 66 patients with PDAC who were operated at our institution. These were subsequently correlated to clinical outcome.

Results

Mean patient age and number of LN harvested was 65.5 ± 10.3 and 12.3 ± 6.5 years, respectively. Tumor size (T stage) and perineural invasion had no effect on clinical outcome. High-grade tumor was associated with decreased survival [overall survival (OS) = 19.6 ± 2.7 months for poorly differentiated PDAC vs. 31.2 ± 4 for well and moderately differentiated, p = 0.03]. Patients with ≥ 8 PLN had significantly worse outcome (OS = 7.3 ± 0.8 months for PLN ≥ 8 vs. OS = 30.1 ± 3.2 months for PLN < 8, p < 0.0001). T helper (Th) 1 immune response was measured both by its effector cells (CD8+) and expression of its main transcription factor, T-bet. CD8+ high patients had significantly increased OS compared with CD8+ low (OS = 36.8 ± 5.3 months for CD8 + high vs. OS = 24.3 ± 3.5 for CD8 + low, p = 0.03) Similarly, Th1 predominant immune response measured by T-bet expression was associated with improved OS compared with non-Th1 (OS = 32.8 ± 3.2 vs. OS = 19.5 ± 2.9, p < 0.0001).

Conclusions

Our data indicate an association between Th1-type immune response and increased survival. Future research is needed to exploit Th1 immune response as a biological marker for immunotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. American Cancer Society. Cancer Facts & Figures. Atlanta: American Cancer Society; 2010.

    Google Scholar 

  2. Werner J, Combs SE, Springfeld C, Hartwig W, Hackert T, Buchler MW. Advanced-stage pancreatic cancer: therapy options. Nat Rev Clin Oncol. 2013;10(6):323–33.

    Article  CAS  PubMed  Google Scholar 

  3. Neoptolemos JP, Palmer DH, Ghaneh P, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389(10073):1011–24.

    Article  CAS  PubMed  Google Scholar 

  4. Benassai G, Mastrorilli M, Quarto G, et al. Factors influencing survival after resection for ductal adenocarcinoma of the head of the pancreas. J Surg Oncol. 2000;73(4):212–18.

    Article  CAS  PubMed  Google Scholar 

  5. Dusch N, Weiss C, Strobel P, Kienle P, Post S, Niedergethmann M. Factors predicting long-term survival following pancreatic resection for ductal adenocarcinoma of the pancreas: 40 years of experience. J Gastrointest Surg. 2014;18(4):674–81.

    Article  PubMed  Google Scholar 

  6. Perysinakis I, Avlonitis S, Georgiadou D, Tsipras H, Margaris I. Five-year actual survival after pancreatoduodenectomy for pancreatic head cancer. ANZ J Surg. 2015;85(3):183–86.

    Article  PubMed  Google Scholar 

  7. Lahat G, Lubezky N, Gerstenhaber F, et al. Number of evaluated lymph nodes and positive lymph nodes, lymph node ratio, and log odds evaluation in early-stage pancreatic ductal adenocarcinoma: numerology or valid indicators of patient outcome? World J Surg Oncol. 2016;14(1):254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Strobel O, Hinz U, Gluth A, et al. Pancreatic adenocarcinoma: number of positive nodes allows to distinguish several N categories. Ann Surg. 2015;261(5):961–69.

    Article  PubMed  Google Scholar 

  9. Basturk O, Saka B, Balci S, et al. Substaging of lymph node status in resected pancreatic ductal adenocarcinoma has strong prognostic correlations: proposal for a revised n classification for TNM staging. Ann Surg Oncol. 2015;22 Suppl 3:S1187–95.

    Article  PubMed  Google Scholar 

  10. Williams JL, Nguyen AH, Rochefort M, et al. Pancreatic cancer patients with lymph node involvement by direct tumor extension have similar survival to those with node-negative disease. J Surg Oncol. 2015;112(4):396–402.

    Article  PubMed  Google Scholar 

  11. Buc E, Couvelard A, Kwiatkowski F, et al. Adenocarcinoma of the pancreas: Does prognosis depend on mode of lymph node invasion? Eur J Surg Oncol. 2014;40(11):1578–85.

    Article  CAS  PubMed  Google Scholar 

  12. Luchini C, Veronese N, Pea A, et al. Extranodal extension in N1-adenocarcinoma of the pancreas and papilla of Vater: a systematic review and meta-analysis of its prognostic significance. Eur J Gastroenterol Hepatol. 2016;28(2):205–09.

    PubMed  Google Scholar 

  13. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  14. Whiteside TL. Immune responses to malignancies. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S272–83.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 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(5795):1960–64.

    Article  CAS  PubMed  Google Scholar 

  16. Kryczek I, Banerjee M, Cheng P, et al. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood. 2009;114(6):1141–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yu P, Fu YX. Tumor-infiltrating T lymphocytes: friends or foes? Lab Invest. 2006;86(3):231–45.

    Article  CAS  PubMed  Google Scholar 

  18. Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348(3):203–13.

    Article  CAS  PubMed  Google Scholar 

  19. Pages F, Berger A, Camus M, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005;353(25):2654–66.

    Article  CAS  PubMed  Google Scholar 

  20. Tosolini M, Kirilovsky A, Mlecnik B, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 2011;71(4):1263–71.

    Article  CAS  PubMed  Google Scholar 

  21. Mahmoud SM, Paish EC, Powe DG, et al. Tumor-infiltrating CD8 + lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29(15):1949–55.

    Article  PubMed  Google Scholar 

  22. Xu Y, Lan S, Zheng Q. Prognostic significance of infiltrating immune cell subtypes in invasive ductal carcinoma of the breast. Tumori. 2017. https://doi.org/10.5301/tj.5000624.

    Google Scholar 

  23. Ino Y, Yamazaki-Itoh R, Shimada K, et al. Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer. 2013;108(4):914–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lazarevic V, Glimcher LH, Lord GM. T-bet: a bridge between innate and adaptive immunity. Nat Rev Immunol. 2013;13(11):777–89.

    Article  CAS  PubMed  Google Scholar 

  25. Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell. 1997;89(4):587–96.

    Article  CAS  PubMed  Google Scholar 

  26. Cochran AJ, Huang RR, Lee J, Itakura E, Leong SP, Essner R. Tumour-induced immune modulation of sentinel lymph nodes. Nat Rev Immunol. 2006;6(9):659–70.

    Article  CAS  PubMed  Google Scholar 

  27. Nizri E, Greenman-Maaravi N, Bar-David S, et al. Analysis of histological and immunological parameters of metastatic lymph nodes from colon cancer patients reveals that T-helper 1 type immune response is associated with improved overall survival. Medicine. 2016;95(45):e5340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bob R, Falini B, Marafioti T, Paterson JC, Pileri S, Stein H. Nodal reactive and neoplastic proliferation of monocytoid and marginal zone B cells: an immunoarchitectural and molecular study highlighting the relevance of IRTA1 and T-bet as positive markers. Histopathology. 2013;63:482–98.

    PubMed  Google Scholar 

  29. Feng Q, Wei H, J. M, et al. Th2 type inflammation promotes the gradual progression of HPV-infected cervical cells to cervical carcinoma. Gynecol Oncol. 2012;127:412-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fu G, Miao L, Wang M, et al. The postoperative immunosuppressive phenotypes of peripheral T-helper cells are associated with poor prognosis of breast cancer patients. Immunol Investig. 2017;47(7):647-62.

    Article  Google Scholar 

  31. Gwela A, Siddhanathi P, Chapman RW, et al. Th1 and innate lymphoid cells accumulate in primary sclerosing cholangitis-associated inflammatory bowel disease. J Crohn’s Colitis. 2017;11(9):1124-34.

    Article  Google Scholar 

  32. Delpero JR, Boher JM, Sauvanet A, et al. Pancreatic adenocarcinoma with venous involvement: is up-front synchronous portal-superior mesenteric vein resection still justified? A survey of the association francaise de chirurgie. Ann Surg Oncol. 2015; 22(6):1874-83.

    Article  PubMed  Google Scholar 

  33. Luttges J, Schemm S, Vogel I, Hedderich J, Kremer B, Kloppel G. The grade of pancreatic ductal carcinoma is an independent prognostic factor and is superior to the immunohistochemical assessment of proliferation. J Pathol. 2000;191(2):154-61.

    Article  CAS  PubMed  Google Scholar 

  34. Rakha EA, El-Sayed ME, Lee AH, et al. Prognostic significance of Nottingham histologic grade in invasive breast carcinoma. J Clin Oncol. 2008;26(19):3153-8.

    Article  PubMed  Google Scholar 

  35. Jass JR, Atkin WS, Cuzick J, et al. The grading of rectal cancer: historical perspectives and a multivariate analysis of 447 cases. Histopathology. 1986;10(5):437-59.

    Article  CAS  PubMed  Google Scholar 

  36. Schorn S, Demir IE, Haller B, et al. The influence of neural invasion on survival and tumor recurrence in pancreatic ductal adenocarcinoma: a systematic review and meta-analysis. Surg Oncol. 2017;26(1):105-15.

    Article  PubMed  Google Scholar 

  37. Johnson BA, 3rd, Yarchoan M, Lee V, Laheru DA, Jaffee EM. Strategies for increasing pancreatic tumor immunogenicity. Clin Cancer Res. 2017;23(7):1656-69.

    Article  PubMed  Google Scholar 

Download references

Disclosures

The authors have nothing do disclose.

Author information

Authors and Affiliations

  1. Division of Surgery, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel

    Eran Nizri MD, PhD, Fabian Gerstenhaber MD, Guy Lahat MD & Joseph Klausner MD

  2. Laboratory of Surgical Oncology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel

    Eran Nizri MD, PhD, Shoshi Bar-David MSc & Guy Lahat MD

  3. Department of Internal Medicine D, Rabin Medical Center-Hasharon Hospital, Petach Tikva, Israel

    Neta Sternbach MD

  4. Department of Surgery, Asaf Harofe Medical Center, Rishon Letzion, Israel

    Amir Ben-Yehuda MD

  5. Institute of Oncology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel

    Tali Ofir MD & Ido Wolf MD

  6. Institute of Pathology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel

    Gilad Weiner MD, PhD

  7. Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Eran Nizri MD, PhD, Ido Wolf MD, Gilad Weiner MD, PhD, Guy Lahat MD & Joseph Klausner MD

  8. The Nikolas and Elizabeth Shlezak Cathedra for Experimental Surgery, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Joseph Klausner MD

Authors
  1. Eran Nizri MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Neta Sternbach MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shoshi Bar-David MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amir Ben-Yehuda MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fabian Gerstenhaber MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tali Ofir MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ido Wolf MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gilad Weiner MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Guy Lahat MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Joseph Klausner MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eran Nizri MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nizri, E., Sternbach, N., Bar-David, S. et al. T-Helper 1 Immune Response in Metastatic Lymph Nodes of Pancreatic Ductal Adenocarcinoma: A Marker For Prolonged Survival. Ann Surg Oncol 25, 475–481 (2018). https://doi.org/10.1245/s10434-017-6237-0

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-017-6237-0

Keywords

Search

Navigation