Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Clinical Studies

Enlarged tumour-draining lymph node with immune-activated profile predict favourable survival in non-metastatic colorectal cancer

Abstract

Background

The tumour-draining lymph node (TDLN) plays a pivotal role in the suppression of malignant tumour, however, the immunological profile and prognostic differences between large TDLN (L-TDLN) and small TDLN (S-TDLN) in colorectal cancer (CRC) remain unclear.

Methods

We conducted a study using data from the Chinese National Cancer Center (CNCC) database, identifying 837 CRC patients with non-metastatic TDLN, and categorised them into L-TDLN and S-TDLN groups. The long-term survival outcomes and adjuvant therapy efficacy were compared between the two groups. Furthermore, we evaluated the differences in immune activation status and immune cell subsets between patients in L-TDLN and S-TDLN groups by RNA sequencing and immunohistochemical (IHC) staining.

Results

Patients with L-TDLN demonstrated better long-term outcomes compared to those with S-TDLN. Among patients with L-TDLN, there was no significant difference in long-term outcomes between those who received adjuvant chemotherapy and those who did not. The RNA sequencing data revealed a wealth of immune-activating pathways explored in L-TDLN. Furthermore, IHC analysis demonstrated higher numbers of CD3+ and CD8 + T cells in L-TDLN and the corresponding CRC lesions, as compared to patients with S-TDLN.

Conclusion

Enlarged TDLN exhibited an activated anti-tumour immune profile and may serve as an indicator for favourable survival in non-metastatic CRC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Workflow of this study about L-TDLN with immune-activated profile in CRC.
Fig. 2: The survival analysis between L-TDLN and S-TDLN group in the CNCC database.
Fig. 3: The analysis on potential biological mechanisms between L-TDLN and S-TDLN group.
Fig. 4: Different characteristics of immune microenvironment cell infiltration between L-TDLN and S-TDLN group.

Similar content being viewed by others

Data availability

The raw CRC patients’ information used in this paper are available from the lead contact upon request. RNA-seq and IHC data are available from the authors on reasonable request and approval of data sharing by institutional review boards. Correspondence for materials should be addressed to the lead contact. Any additional information required to reanalyse the data reported in this paper is available from the lead contact upon request.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49. https://doi.org/10.3322/caac.21660.

    Article  PubMed  Google Scholar 

  2. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10. https://doi.org/10.1016/j.immuni.2013.07.012.

    Article  CAS  PubMed  Google Scholar 

  3. Förster R, Braun A, Worbs T. Lymph node homing of T cells and dendritic cells via afferent lymphatics. Trends Immunol. 2012;33:271–80. https://doi.org/10.1016/j.it.2012.02.007.

    Article  CAS  PubMed  Google Scholar 

  4. Dammeijer F, van Gulijk M, Mulder EE, Lukkes M, Klaase L, van den Bosch T, et al. The PD-1/PD-L1-checkpoint restrains T cell immunity in tumor-draining lymph nodes. Cancer Cell. 2020;38:685–700.e688. https://doi.org/10.1016/j.ccell.2020.09.001.

    Article  CAS  PubMed  Google Scholar 

  5. van Pul KM, Vuylsteke R, van de Ven R, Te Velde EA, Rutgers EJT, van den Tol PM, et al. Selectively hampered activation of lymph node-resident dendritic cells precedes profound T cell suppression and metastatic spread in the breast cancer sentinel lymph node. J Immunother Cancer. 2019;7:133 https://doi.org/10.1186/s40425-019-0605-1.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kohrt HE, Nouri N, Nowels K, Johnson D, Holmes S, Lee PP. Profile of immune cells in axillary lymph nodes predicts disease-free survival in breast cancer. PLoS Med. 2005;2:e284 https://doi.org/10.1371/journal.pmed.0020284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chen YY, Ge JY, Ma D, Yu KD. Immune-activated regional lymph nodes predict favorable survival in early-stage triple-negative breast cancer. Front Oncol. 2020;10:570981 https://doi.org/10.3389/fonc.2020.570981.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Märkl B, Paul B, Schaller T, Kretsinger H, Kriening B, Schenkirsch G. The role of lymph node size and FOXP3+ regulatory T cells in node-negative colon cancer. J Clin Pathol. 2017;70:443–7. https://doi.org/10.1136/jclinpath-2016-203978.

    Article  CAS  PubMed  Google Scholar 

  9. Märkl B, Rößle J, Arnholdt HM, Schaller T, Krammer I, Cacchi C, et al. The clinical significance of lymph node size in colon cancer. Mod Pathol. 2012;25:1413–22. https://doi.org/10.1038/modpathol.2012.92.

    Article  CAS  PubMed  Google Scholar 

  10. Hanke T, Melling N, Simon R, Sauter G, Bokemeyer C, Lebok P, et al. High intratumoral FOXP3+ T regulatory cell (Tregs) density is an independent good prognosticator in nodal negative colorectal cancer. Int J Clin Exp Pathol. 2015;8:8227–35.

    PubMed  PubMed Central  Google Scholar 

  11. Holm JB, Humphrys MS, Robinson CK, Settles ML, Ott S, Fu L, et al. Ultrahigh-throughput multiplexing and sequencing of >500-base-pair amplicon regions on the Illumina HiSeq 2500 platform. mSystems. 2019;4. https://doi.org/10.1128/msystems.00029-19.

  12. Bao Y, Wang L, Shi L, Yun F, Liu X, Chen Y, et al. Transcriptome profiling revealed multiple genes and ECM-receptor interaction pathways that may be associated with breast cancer. Cell Mol Biol Lett. 2019;24:38 https://doi.org/10.1186/s11658-019-0162-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hänzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinforma. 2013;14:7 https://doi.org/10.1186/1471-2105-14-7.

    Article  Google Scholar 

  14. Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453–7. https://doi.org/10.1038/nmeth.3337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wei R, Li S, Yu G, Guan X, Liu H, Quan J, et al. Deciphering the pyroptosis-related prognostic signature and immune cell infiltration characteristics of colon cancer. Front Genet. 2021;12:755384 https://doi.org/10.3389/fgene.2021.755384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li T, Fu J, Zeng Z, Cohen D, Li J, Chen Q, et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 2020;48:W509–w514. https://doi.org/10.1093/nar/gkaa407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, et al. TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res. 2017;77:e108–e110. https://doi.org/10.1158/0008-5472.can-17-0307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Li B, Severson E, Pignon JC, Zhao H, Li T, Novak J, et al. Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome Biol. 2016;17:174 https://doi.org/10.1186/s13059-016-1028-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007;370:1453–7. https://doi.org/10.1136/bmj.39335.541782.ad.

    Article  PubMed  Google Scholar 

  20. Huynh KT, Bilchik AJ. Sentinel lymph node biopsy and nodal ultrastaging in colorectal cancer. Cancer J. 2015;21:11–16. https://doi.org/10.1097/ppo.0000000000000093.

    Article  PubMed  Google Scholar 

  21. Chen Y, Wen Z, Ma Y, Liu Y, Que Y, Yang X, et al. Metastatic lymph node calcification in rectal cancer: comparison of CT and high-resolution MRI. Jpn J Radiol. 2021;39:642–51. https://doi.org/10.1007/s11604-021-01108-6.

    Article  PubMed  Google Scholar 

  22. Christou N, Meyer J, Toso C, Ris F, Buchs NC. Lateral lymph node dissection for low rectal cancer: is it necessary? World J Gastroenterol. 2019;25:4294–9. https://doi.org/10.3748/wjg.v25.i31.4294.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Märkl B. Stage migration vs immunology: the lymph node count story in colon cancer. World J Gastroenterol. 2015;21:12218–33. https://doi.org/10.3748/wjg.v21.i43.12218.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Inamori K, Togashi Y, Fukuoka S, Akagi K, Ogasawara K, Irie T, et al. Importance of lymph node immune responses in MSI-H/dMMR colorectal cancer. JCI Insight 2021;6. https://doi.org/10.1172/jci.insight.137365.

  25. Piersiala K, Farrajota Neves da Silva P, Hjalmarsson E, Kolev A, Kågedal Å, Starkhammar M, et al. CD4(+) and CD8(+) T cells in sentinel nodes exhibit distinct pattern of PD-1, CD69, and HLA-DR expression compared to tumor tissue in oral squamous cell carcinoma. Cancer Sci. 2021;112:1048–59. https://doi.org/10.1111/cas.14816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sato D, Shimoyamada M, Ito Y, Yoshida S, Ishida H, Yamaguchi T, et al. [Reactive swelling of the regional lymph nodes in patients with stage II colorectal cancer as a prognostic factor]. Nihon Shokakibyo Gakkai Zasshi. 2017;114:1629–38. https://doi.org/10.11405/nisshoshi.114.1629.

    Article  PubMed  Google Scholar 

  27. Ruisch JE, Kloft M, Fazzi GE, Melenhorst J, Magee DR, Grabsch HI. Large negative lymph nodes - a surrogate for immune activation in rectal cancer patients? Pathol Res Pr. 2020;216:153106 https://doi.org/10.1016/j.prp.2020.153106.

    Article  CAS  Google Scholar 

  28. Deschoolmeester V, Baay M, Lardon F, Pauwels P, Peeters M. Immune cells in colorectal cancer: prognostic relevance and role of MSI. Cancer Microenviron. 2011;4:377–92. https://doi.org/10.1007/s12307-011-0068-5.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–8. https://doi.org/10.1126/science.aaa1348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EM, Putter H, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011;12:575–82. https://doi.org/10.1016/s1470-2045(11)70097-3.

    Article  PubMed  Google Scholar 

  31. Bregni G, Akin Telli T, Camera S, Deleporte A, Moretti L, Bali AM, et al. Adjuvant chemotherapy for rectal cancer: current evidence and recommendations for clinical practice. Cancer Treat Rev. 2020;83:101948 https://doi.org/10.1016/j.ctrv.2019.101948.

    Article  CAS  PubMed  Google Scholar 

  32. Jiang D, Gao T, Liang S, Mu W, Fu S, Liu Y, et al. Lymph node delivery strategy enables the activation of cytotoxic T lymphocytes and natural killer cells to augment cancer immunotherapy. ACS Appl Mater Interfaces. 2021;13:22213–24. https://doi.org/10.1021/acsami.1c03709.

    Article  CAS  PubMed  Google Scholar 

  33. Buckowitz A, Knaebel HP, Benner A, Bläker H, Gebert J, Kienle P, et al. Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases. Br J Cancer. 2005;92:1746–53. https://doi.org/10.1038/sj.bjc.6602534.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hong EK, Chalabi M, Landolfi F, Castagnoli F, Park SJ, Sikorska K, et al. Colon cancer CT staging according to mismatch repair status: comparison and suggestion of imaging features for high-risk colon cancer. Eur J Cancer. 2022;174:165–75. https://doi.org/10.1016/j.ejca.2022.06.060.

    Article  PubMed  Google Scholar 

  35. Stintzing S, Wirapati P, Lenz HJ, Neureiter D, Fischer von Weikersthal L, Decker T, et al. Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial. Ann Oncol. 2019;30:1796–803. https://doi.org/10.1093/annonc/mdz387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors have not acknowledgement to make.

Funding

This study was supported by the National Key R&D Program for Young Scientists (Grant Number: 2022YFC2505700), the National Natural Science Foundation of China (Grant Number: 82100598), Beijing Hope Run Special Fund of Cancer Foundation of China (LC2021A23) and the Sanming Project of Medicine in Shenzhen (Grant Number: No. SZSM201911012).

Author information

Authors and Affiliations

Authors

Contributions

Conceptualisation: XSW, SMZ, ZXZ, ZJ and XG; methodology: XG, PC and RW.; formal analysis: XG, PC and RW; resources: XG, PC, RW, JTL, SJ, ZXZ, HPC and ZL; writing—original draft: XG, PC and RW; writing—review and editing: XG, PC and RW; funding acquisition: XSW, SMZ, ZXZ, ZJ and XG; supervision: XSW, SMZ, ZXZ, ZJ and XG.

Corresponding authors

Correspondence to Zheng Jiang, Zhaoxu Zheng, Shuangmei Zou or Xishan Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This study has been approved by the Ethics Committee of Cancer Hospital, Chinese Academy of Medical Sciences (Approval ID: 23/139–3881). The access to and use of SEER data did not require informed patient consent.

Consent for publication

Not applicable.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guan, X., Cheng, P., Wei, R. et al. Enlarged tumour-draining lymph node with immune-activated profile predict favourable survival in non-metastatic colorectal cancer. Br J Cancer 130, 31–42 (2024). https://doi.org/10.1038/s41416-023-02473-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-023-02473-x

Search

Quick links