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Integrative analysis identifies activated anti-tumor immune microenvironment in lung metastasis of pancreatic cancer

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Abstract

Background

Although the prognosis of patients experiencing recurrences after surgery for pancreatic cancer is extremely poor, patients who develop recurrence in the lung have a better prognosis compared to other types of recurrence. We performed a histo-immunological analysis of the metastatic specimens to identify specific features of this patient subgroup.

Methods

We performed immunohistochemistry for CD4+, CD8+, CD45RO+, Foxp3, and PD-L1 in the lung (n = 22), peritoneal (n = 18), and liver (n = 6) metastases of pancreatic cancer. As microenvironmental and immunonutritional investigations, the tumor-stroma ratio and prognostic nutritional index (PNI) were utilized in the integrative analysis of immunological features.

Results

We identified significantly increased tumor-infiltrating CD4+, CD8+, and CD45RO+ cells in lung metastasis, compared with peritoneal and liver metastases (lung vs. peritoneum/liver, CD4: P < 0.001/P = 0.015, CD8: P < 0.001/P = 0.038, CD45RO: P = 0.022/P = 0.012). The CD8/Foxp3 ratio was higher in the lung than in the liver (P = 0.024). PD-L1 expression was significantly higher in lung metastasis than in peritoneal metastasis (P = 0.010). Furthermore, we found that lung metastasis had fewer cancer stroma than peritoneal metastasis (P < 0.001). A higher PNI was observed in patients with lung metastasis, and PNI was positively correlated with tumor-infiltrating lymphocytes in metastatic sites.

Conclusion

We identified that lung metastasis revealed an immunologically “hot” tumor with increased TILs and PD-L1 expression. This specific feature suggests that patients with lung metastasis can be candidates for immunotherapy, such as immune checkpoint inhibitors; therefore, our study provides a framework for developing individualized treatment strategies for this patient subgroup.

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Authors and Affiliations

  1. Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan

    Toshihide Sasaki, Satoshi Nishiwada, Kenji Nakagawa, Minako Nagai, Taichi Terai, Daisuke Hokuto, Satoshi Yasuda, Yasuko Matsuo, Shunsuke Doi & Masayuki Sho

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  1. Toshihide Sasaki
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  2. Satoshi Nishiwada
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  3. Kenji Nakagawa
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Contributions

Toshihide Sasaki: study concept and design; acquisition of clinical data; analysis and interpretation of data and statistical analysis; drafting of the manuscript. Satoshi Nishiwada: study concept and design; specimen providers; acquisition of clinical data; analysis and interpretation of data and statistical analysis; drafting of the manuscript. Kenji Nakagawa: specimen providers; acquisition of clinical data. Minako Nagai: specimen providers; acquisition of clinical data. Taichi Terai: specimen providers; acquisition of clinical data. Daisuke Hokuto: specimen providers; acquisition of clinical data. Satoshi Yasuda: specimen providers; acquisition of clinical data. Yasuko Matsuo: specimen providers; acquisition of clinical data. Shunsuke Doi: specimen providers; acquisition of clinical data. Masayuki Sho: study concept and design; specimen providers; acquisition of clinical data; drafting of the manuscript; revision of the article; final approval of the article. All the authors have read and approved the final manuscript.

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Correspondence to Masayuki Sho.

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Supplementary Information

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10147_2022_2131_MOESM1_ESM.pdf

Supplementary Fig. 1 Cumulative recurrence rate after primary tumor resection in pancreatic cancer. Recurrence was significantly later in patients with lung metastasis than in patients with peritoneal, liver, and multi-site metastasis. ‡P < 0.01, §P < 0.001 (PDF 27 KB)

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Sasaki, T., Nishiwada, S., Nakagawa, K. et al. Integrative analysis identifies activated anti-tumor immune microenvironment in lung metastasis of pancreatic cancer. Int J Clin Oncol 27, 948–957 (2022). https://doi.org/10.1007/s10147-022-02131-x

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  • DOI: https://doi.org/10.1007/s10147-022-02131-x

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