PMID- 29279354 OWN - NLM STAT- MEDLINE DCOM- 20190116 LR - 20210103 IS - 1538-7445 (Electronic) IS - 0008-5472 (Linking) VI - 78 IP - 5 DP - 2018 Mar 1 TI - Germinal Centers Determine the Prognostic Relevance of Tertiary Lymphoid Structures and Are Impaired by Corticosteroids in Lung Squamous Cell Carcinoma. PG - 1308-1320 LID - 10.1158/0008-5472.CAN-17-1987 [doi] AB - In solid tumors, the presence of lymph node-like structures called tertiary lymphoid structures (TLS) is associated with improved patient survival. However, little is known about how TLS develop in cancer, how their function affects survival, and whether they are affected by cancer therapy. In this study, we used multispectral microscopy, quantitative pathology, and gene expression profiling to analyze TLS formation in human lung squamous cell carcinoma (LSCC) and in an experimental model of lung TLS induction. We identified a niche of CXCL13(+) perivascular and CXCL12(+)LTB(+) and PD-L1(+) epithelial cells supporting TLS formation. We also characterized sequential stages of TLS maturation in LSCC culminating in the formation of germinal centers (GC). In untreated patients, TLS density was the strongest independent prognostic marker. Furthermore, TLS density correlated with GC formation and expression of adaptive immune response-related genes. In patients treated with neoadjuvant chemotherapy, TLS density was similar, but GC formation was impaired and the prognostic value of TLS density was lost. Corticosteroids are coadministered with chemotherapy to manage side effects in LSCC patients, so we evaluated whether they impaired TLS development independently of chemotherapy. TLS density and GC formation were each reduced in chemotherapy-naive LSCC patients treated with corticosteroids before surgery, compared with untreated patients, a finding that we confirmed in the experimental model of lung TLS induction. Overall, our results highlight the importance of GC formation in TLS during tumor development and treatment.Significance: Corticosteroid treatment during chemotherapy negatively affects the development of tertiary lymphoid structures and abrogates their prognostic value in patients with lung cancer. Cancer Res; 78(5); 1308-20. (c)2018 AACR. CI - (c)2018 American Association for Cancer Research. FAU - Silina, Karina AU - Silina K AD - Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. FAU - Soltermann, Alex AU - Soltermann A AD - Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland. FAU - Attar, Farkhondeh Movahedian AU - Attar FM AD - Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. FAU - Casanova, Ruben AU - Casanova R AD - Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland. FAU - Uckeley, Zina M AU - Uckeley ZM AD - Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. FAU - Thut, Helen AU - Thut H AD - Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. FAU - Wandres, Muriel AU - Wandres M AD - Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. FAU - Isajevs, Sergejs AU - Isajevs S AD - Pathology Center, Riga East Clinical University Hospital, Riga, Latvia. AD - Faculty of Medicine, University of Latvia, Riga, Latvia. FAU - Cheng, Phil AU - Cheng P AD - Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. FAU - Curioni-Fontecedro, Alessandra AU - Curioni-Fontecedro A AD - Department of Oncology, University Hospital Zurich, Zurich, Switzerland. FAU - Foukas, Periklis AU - Foukas P AD - Department of Oncology, CHUV-UNIL, Lausanne, Switzerland. AD - Department of Pathology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece. FAU - Levesque, Mitchell P AU - Levesque MP AD - Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. FAU - Moch, Holger AU - Moch H AD - Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland. FAU - Line, Aija AU - Line A AD - Latvian Biomedical Research and Study Center, Riga, Latvia. FAU - van den Broek, Maries AU - van den Broek M AD - Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. vandenbroek@immunology.uzh.ch. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171226 PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 0 (Adrenal Cortex Hormones) SB - IM MH - Adrenal Cortex Hormones/*adverse effects MH - Aged MH - Animals MH - Antineoplastic Combined Chemotherapy Protocols/therapeutic use MH - Apoptosis MH - Carcinoma, Non-Small-Cell Lung/drug therapy/immunology/*pathology MH - Carcinoma, Squamous Cell/drug therapy/immunology/*pathology MH - Cell Proliferation MH - Female MH - Follow-Up Studies MH - Gene Expression Profiling MH - Germinal Center/drug effects/immunology/*pathology MH - Humans MH - Lung Neoplasms/drug therapy/immunology/*pathology MH - Lymphocytes, Tumor-Infiltrating/*immunology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Middle Aged MH - Prognosis MH - Survival Rate MH - Tertiary Lymphoid Structures/chemically induced/immunology/*pathology MH - Tumor Cells, Cultured MH - Tumor Microenvironment MH - Xenograft Model Antitumor Assays EDAT- 2017/12/28 06:00 MHDA- 2019/01/17 06:00 CRDT- 2017/12/28 06:00 PHST- 2017/07/04 00:00 [received] PHST- 2017/11/01 00:00 [revised] PHST- 2017/12/19 00:00 [accepted] PHST- 2017/12/28 06:00 [pubmed] PHST- 2019/01/17 06:00 [medline] PHST- 2017/12/28 06:00 [entrez] AID - 0008-5472.CAN-17-1987 [pii] AID - 10.1158/0008-5472.CAN-17-1987 [doi] PST - ppublish SO - Cancer Res. 2018 Mar 1;78(5):1308-1320. doi: 10.1158/0008-5472.CAN-17-1987. Epub 2017 Dec 26.