Germinal Centers Determine the Prognostic Relevance of Tertiary Lymphoid Structures and Are Impaired by Corticosteroids in Lung Squamous Cell Carcinoma

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 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 CXCL12LTB 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-naïve 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. Corticosteroid treatment during chemotherapy negatively affects the development of tertiary lymphoid structures and abrogates their prognostic value in patients with lung cancer. .

APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures

“…It was further shown that lung squamous cell carcinoma patients have less germinal centers in their TLS if they received cisplatin-based neoadjuvant chemotherapy, but the chemotherapy was co-administered with corticosteroids that could have a direct inhibitor effect on germinal center maturation. 30 To our knowledge, our observation is the first description of chemotherapy-induced TLS formation with paired prechemotherapy biopsies as a control, indicating that chemotherapy induces a peculiar immune response. This could involve the socalled immunogenic cell death (ICD), a class of controlled cell death processes that produce damage-associated molecular patterns which can act as adjuvants for initiating the immune response via the recruitment and activation of dendritic cells.…”

“…26 While it has been known for a long time that chemotherapy can increase the number of tumor -infiltrating lymphocytes in different neoplasms such as breast 27 or ovarian cancer, 28 the effect of neoadjuvant chemotherapy on TLS is poorly documented. In different types of lung cancers, 29,30 intratumor TLS have been described both in the presence and the absence of chemotherapy. It was further shown that lung squamous cell carcinoma patients have less germinal centers in their TLS if they received cisplatin-based neoadjuvant chemotherapy, but the chemotherapy was co-administered with corticosteroids that could have a direct inhibitor effect on germinal center maturation.…”

Helper T cell-dominant tertiary lymphoid structures are associated with disease relapse of advanced colorectal cancer

“…Since there is no established TLS classification, previous studies adopted their own classifications. 12,25,26 One previous report of ovarian cancer classified lymphoid aggregates into four types based on size, cellular composition, and degree of GC organization. 25 The authors examined the associations between the four types and tumor infiltrating lymphocytes (TILs) and plasma cell densities, whereas they did not mention the relationships of the four types to clinical outcomes.…”

Tumor-associated tertiary lymphoid structure predicts postoperative outcomes in patients with primary gastrointestinal stromal tumors

“…51 In contrast, caution is advised when administrating corticosteroids to manage chemotherapy side effects, as it could decrease the density of TLS in patients with lung squamous cell carcinomas. 52 These findings are valuable to help us develop immunotherapies that specifically enables the formation of TLS to improve the prognosis of patients with GIST.…”