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. 2023 Jun;72(6):1823-1834.
doi: 10.1007/s00262-022-03353-8. Epub 2023 Jan 23.

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

Sho Wakasu  1   2 , Tetsuzo Tagawa  3 , Naoki Haratake  1 , Fumihiko Kinoshita  1 , Yuka Oku  1 , Yuki Ono  1 , Tomoyoshi Takenaka  1 , Yoshinao Oda  2 , Mototsugu Shimokawa  4 , Masaki Mori  1
Affiliations

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

Sho Wakasu et al. Cancer Immunol Immunother. 2023 Jun.

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.

Keywords: Cytotoxic lymphocyte; Lung adenocarcinoma; Lymph node metastasis; Tertiary lymphoid structure.

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Conflict of interest statement

None.

Figures

Fig. 1
Fig. 1
Characterization of tertiary lymphoid structures and tumor-infiltrating lymphocytes. Characterization of tertiary lymphoid structures (TLSs) in lung adenocarcinoma by staining of formalin-fixed, paraffin-embedded tissues (A–D). TLS in lung adenocarcinoma stained by hematoxylin and eosin (A), CD20 (B), CD3 (C) and DC-Lamp (D). Tumor-infiltrating lymphocytes stained by CD3 (E), CD8 (F), CD4 (G) and Foxp3 (H). Histogram of the number of TLSs within low-power field (LPF) (I). Histogram of the number of DC-Lamp+ mature dendritic cells in TLSs (/0.04 mm2) (J)
Fig. 2
Fig. 2
The maturation of tertiary lymphoid structure relates to prognosis. Kaplan–Meier curves of overall survival (A) and disease-free survival (B) for patients with lung adenocarcinoma depending on mature/immature tertiary lymphoid structure. *P < 0.05
Fig. 3
Fig. 3
The relationship between the maturation of tertiary lymphoid structure and cytotoxic lymphocytes. The mean number of peripheral cytotoxic lymphocytes in non-metastatic lymph nodes (LNs) depending on mature/immature tertiary lymphoid structures (TLSs) (A) and LN metastasis (+ / −) (B). Characterization of cytotoxic lymphocytes stained by granzyme B in LNs (C–E). The number of cytotoxic lymphocytes in LNs at the center and periphery (F). Characterization of cytotoxic lymphocytes stained by granzyme B in TLS (G) and tumor-infiltrating lymphocytes (TILs) (H). The mean number of cytotoxic lymphocytes in TLSs (I) and TILs (J) depending on mature/immature TLS. *P < 0.05. **P, C, M in Fig. 3C-E mean periphery of LN, center of LN and metastasized lesion, respectively
See this image and copyright information in PMC

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