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Germinal centers determine the prognostic relevance of tertiary lymphoid structures and are impaired by corticosteroids in lung squamous cell carcinoma


Silina, Karina; Soltermann, Alex; Movahedian Attar, Farkhondeh; Casanova, Ruben; Uckeley, Zina M; Thut, Helen; Wandres, Muriel; Isajevs, Sergejs; Cheng, Phil F; Curioni Fontecedro, Alessandra; Foukas, Periklis; Levesque, Mitchell P; Moch, Holger; Linē, Aija; van den Broek, Maries (2018). Germinal centers determine the prognostic relevance of tertiary lymphoid structures and are impaired by corticosteroids in lung squamous cell carcinoma. Cancer Research, 78(5):1308-1320.

Abstract

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 form in cancer, how their function affects survival, and whether they are affected by cancer therapy. In this study, we used multi-spectral 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. Further, 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 co-administered 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 to 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.

Abstract

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 form in cancer, how their function affects survival, and whether they are affected by cancer therapy. In this study, we used multi-spectral 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. Further, 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 co-administered 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 to 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2018
Deposited On:09 Feb 2018 07:47
Last Modified:04 Sep 2018 13:01
Publisher:American Association for Cancer Research
ISSN:0008-5472
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1158/0008-5472.CAN-17-1987
PubMed ID:29279354
Project Information:
  • : FunderSNSF
  • : Grant ID31003A_152851
  • : Project TitleThe impact of radio- and immunotherapy on local tumor-specific immunity

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