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Preventive effect of tertiary lymphoid structures on lymph node metastasis of lung adenocarcinoma

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Abstract

Background

Ectopic lymphoid formations are called tertiary lymphoid structures (TLSs). TLSs in cancer have been reported to be associated with good prognosis and immunotherapy response. However, the relationship between TLSs and lymph node (LN) metastasis is unclear.

Methods

We analyzed 218 patients with radically resected lung adenocarcinoma. TLSs were defined as the overlap of T cell zone and B cell zone. Granzyme B + cells were defined as cytotoxic lymphocytes. We evaluated phenotypes of lymphocytes in TLSs, tumor-infiltrating lymphocytes (TILs) and LNs by immunohistochemistry. We divided the patients into mature TLS (DC-Lamp high) and immature TLS (DC-Lamp low) groups. The relationship between TLS maturation and clinicopathological factors was analyzed.

Results

The mature TLS group was associated with significantly lower frequency of LN metastasis (P < 0.0001) and early cancer stage (P = 0.0049). The mature TLS group had significantly more CD8 + (P = 0.0203) and Foxp3 + (P = 0.0141) cells in TILs than the immature TLS group had. Mature TLSs were independently associated with a favorable overall survival (hazard ratio [HR] = 0.17, P = 0.0220) and disease-free survival (HR = 0.54, P = 0.0436). Multivariate analysis showed that mature TLS was an independent low-risk factor for LN metastasis (odds ratio = 0.06, P = 0.0003). The number of cytotoxic lymphocytes in LNs was higher in the mature TLS group than in the immature group (20.0 vs. 15.1, P = 0.017).

Conclusion

Mature TLSs were associated with an increased number of cytotoxic lymphocytes in draining LNs, a lower frequency of LN metastasis, and favorable outcomes. Mature TLSs may support antitumor immunity by lymphocyte activation.

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Data availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

DC:

Dendritic cell

DFS:

Disease-free survival

HEV:

High endothelial venule

HR:

Hazard ratio

LN:

Lymph node

LT:

Lymphotoxin.

OR:

Odds ratio

OS:

Overall survival

PD-L1:

Programmed cell death-ligand 1

pN:

Pathological N status

pT:

Pathological T status

TIL:

Tumor-infiltrating lymphocyte

TLS:

Tertiary lymphoid structure

TNF:

Tumor necrosis factor

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Acknowledgements

We thank MN and YK for her invaluable help with tissue processing. We also thank CK, BSc, PhD, from Edanz Group (https://en-author-services.edanzgroup.com/ac) for editing a draft of this manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan

    Sho Wakasu, Tetsuzo Tagawa, Naoki Haratake, Fumihiko Kinoshita, Yuka Oku, Yuki Ono, Tomoyoshi Takenaka & Masaki Mori

  2. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Sho Wakasu & Yoshinao Oda

  3. Department of Biostatistics, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan

    Mototsugu Shimokawa

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  1. Sho Wakasu
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Contributions

Conception and design: SW, TT, MM. Development of methodology: SW, FK, TT, YO. Acquisition of data: SW, YO, YO, FK. Analysis and interpretation of data: SW, FK, NH, TT, TT, YO, MS, MM. Writing, review, and/or revision of manuscript: SW, FK, NH, TT, YO, MM. Study supervision: TT, MS, YO, MM.

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Correspondence to Tetsuzo Tagawa.

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This study was approved by our Institutional Review Board (Kyushu University, IRB No. 2019–232).

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Wakasu, S., Tagawa, T., Haratake, N. et al. Preventive effect of tertiary lymphoid structures on lymph node metastasis of lung adenocarcinoma. Cancer Immunol Immunother 72, 1823–1834 (2023). https://doi.org/10.1007/s00262-022-03353-8

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