IA19 Evaluating the Role of B Cells and Tertiary Lymphoid Structures in Lung Cancer Development and Progression

Immune profile of B and T cells and tertiary lymphoid structures (TLSs) may differ in tumors of lung cancer (LC) patients with/without chronic obstructive pulmonary disease (COPD), and may also influence patient survival. We sought to analyze: (1) TLSs, germinal centers (GCs), B and T cells, and (2) associations of the immune biomarkers with the patients’ 10-year overall survival (OS). TLSs (numbers and area), B [cluster of differentiation (CD) 20], and T (CD3), and GCs cells were identified in both tumor and non-tumor specimens (thoracotomy) from 90 LC-COPD patients and 43 LC-only patients. Ten-year OS was analyzed in the patients. Immune profile in tumors of LC-COPD versus LC: TLS numbers and areas significantly decreased in tumors of LC-COPD compared to LC patients. No significant differences were observed in tumors between LC-COPD and LC patients for B or T cells. Immune profile in tumors versus non-tumor specimens: TLS areas and B cells significantly increased, T cells significantly decreased in tumors of both LC and LC-COPD patients. Survival: in LC-COPD patients: greater area of TLSs and proportion of B cells were associated with longer survival rates. The immune tumor microenvironment differs in patients with underlying COPD and these different phenotypes may eventually impact the response to immunotherapy in patients with LC.

Download Full-text

Abstract 73: Targeting B Cells and Tertiary Lymphoid Structures in Lung Cancer Progression

10.1158/1538-7755.asgcr21-73 ◽

2021 ◽

Author(s):

Tullia Bruno ◽

Dongyan Liu ◽

Sheryl Kunning ◽

Riyue Bao ◽

Laura Stabile ◽

...

Keyword(s):

Lung Cancer ◽

B Cells ◽

Cancer Progression ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures

Download Full-text

Divergent cancer etiologies drive distinct B cell signatures and tertiary lymphoid structures

10.1101/2020.05.29.123265 ◽

2020 ◽

Author(s):

Ayana T Ruffin ◽

Anthony R Cillo ◽

Tracy Tabib ◽

Angen Liu ◽

Sayali Onkar ◽

...

Keyword(s):

B Cells ◽

Single Cell ◽

Antitumor Immunity ◽

Spatial Organization ◽

Environmental Carcinogens ◽

Transitional State ◽

Rnaseq Data ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures

AbstractCurrent immunotherapy paradigms aim to reinvigorate CD8+ T cells, but the contribution of humoral immunity to antitumor immunity remains understudied1,2. Head and neck squamous cell carcinoma (HNSCC) is caused by either human papillomavirus (HPV+) or environmental carcinogens (i.e. tobacco and alcohol; HPV–)3,4. Here, we demonstrate that HPV+ HNSCC patients have transcriptional signatures of germinal center (GC) tumor infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with GC-like tertiary lymphoid structures (TLS), both of which correlate with favorable outcomes in HNSCC patients. Further, our single-cell RNAseq data also indicate that GC TIL-Bs are characterized by distinct waves of gene expression consistent with dark zone, light zone and a transitional state of GC B cells. High-dimensional spectral flow cytometry permitted in depth characterization of activated, memory and GC TIL-Bs. Further, single cell RNAseq analysis and subsequent protein validation identified a role for semaphorin 4a (Sema4a) in the differentiation of GC TIL-Bs and indicated that expression of Sema4a was enhanced on GC TIL-Bs and within GC-like TLS in the TME. Thus, in contrast to some reports on the detrimental role of TIL-Bs in human tumors, our findings suggest that TIL-Bs play an instrumental role in antitumor immunity5,6. Novel therapeutics to enhance TIL-B responses in HNSCC should be prioritized as a compliment to current T-cell mediated immunotherapies.

Download Full-text

Abstract A62: Investigating the role of follicular helper T cells, B cells and CXCL13 in breast cancer-associated tertiary lymphoid structures

10.1158/2326-6074.tumimm16-a62 ◽

2017 ◽

Author(s):

Edoardo Migliori ◽

Chunyan Gu-Trantien ◽

Soizic Garaud ◽

Gert Van den Eynden ◽

Alexandre De Wind ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

B Cells ◽

Helper T Cells ◽

Follicular Helper T Cells ◽

Follicular Helper ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures

Download Full-text

Tertiary lymphoid structures critical for prognosis in endometrial cancer patients - a TransPORTEC study

10.21203/rs.3.rs-677975/v1 ◽

2021 ◽

Author(s):

Nanda Horeweg ◽

Hagma Workel ◽

Dominik Loiero ◽

David Church ◽

Lisa Vermij ◽

...

Keyword(s):

Endometrial Cancer ◽

B Cells ◽

Cox Regression ◽

Pivotal Role ◽

Prognostic Impact ◽

Cox Regression Analysis ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures ◽

L1cam Expression

Abstract B-cells play a key role in cancer suppression, particularly when aggregated in tertiary lymphoid structures (TLS). Here, we investigated the role of B-cells and TLS in endometrial cancer (EC). Single cell RNA-sequencing of B-cells showed presence of activated/memory B-cells, cycling/germinal center B-cells and antibody-secreting cells. Differential gene expression analysis showed association of TLS with L1CAM overexpression. Immunohistochemistry and co-immunofluorescence showed L1CAM expression in mature TLS localized in the myometrial wall or at the tumor invasive border, independent of L1CAM expression the tumor. Using L1CAM as a marker, 378 of the 411 molecularly classified ECs from the PORTEC-3 biobank were evaluated. TLS were found in 19%, predominantly in mismatch-repair deficient and polymerase-epsilon mutant EC. Multivariable Cox regression analysis showed strong favorable prognostic impact of TLS, independent of clinicopathological and molecular factors. Our data suggests a pivotal role of TLS in outcome of EC patients, and establishes L1CAM as a simple biomarker.Statement of significance Tertiary lymphoid structures have a pivotal role in the immune response against endometrial cancer. Presence of mature tertiary lymphoid structures can be easily assessed using L1CAM immunohistochemistry and has independent favorable predictive value for recurrence and endometrial cancer-specific survival.

Download Full-text

Tertiary Lymphoid Structures in Cancer: The Double-Edged Sword Role in Antitumor Immunity and Potential Therapeutic Induction Strategies

Frontiers in Immunology ◽

10.3389/fimmu.2021.689270 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wendi Kang ◽

Zhichao Feng ◽

Jianwei Luo ◽

Zhenhu He ◽

Jun Liu ◽

...

Keyword(s):

Poor Prognosis ◽

Antitumor Immunity ◽

Close Association ◽

Germinal Centers ◽

Vital Role ◽

Cancer Development ◽

Multiple Strategies ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures

The complex tumor microenvironment (TME) plays a vital role in cancer development and dramatically determines the efficacy of immunotherapy. Tertiary lymphoid structures (TLSs) within the TME are well recognized and consist of T cell-rich areas containing dendritic cells (DCs) and B cell-rich areas containing germinal centers (GCs). Accumulating research has indicated that there is a close association between tumor-associated TLSs and favorable clinical outcomes in most types of cancers, though a minority of studies have reported an association between TLSs and a poor prognosis. Overall, the double-edged sword role of TLSs in the TME and potential mechanisms need to be further investigated, which will provide novel therapeutic perspectives for antitumor immunoregulation. In this review, we focus on discussing the main functions of TLSs in the TME and recent advances in the therapeutic manipulation of TLSs through multiple strategies to enhance local antitumor immunity.

Download Full-text

Differential Impacts of Insulin-Like Growth Factor-Binding Protein-3 (IGFBP-3) in Epithelial IGF-Induced Lung Cancer Development

Endocrinology ◽

10.1210/en.2010-0693 ◽

2011 ◽

Vol 152 (6) ◽

pp. 2164-2173 ◽

Cited By ~ 13

Author(s):

Woo-Young Kim ◽

Mi-Jung Kim ◽

Hojin Moon ◽

Ping Yuan ◽

Jin-Soo Kim ◽

...

Keyword(s):

Lung Cancer ◽

Lung Tumor ◽

Binding Protein ◽

Cancer Development ◽

Lung Carcinogenesis ◽

Tobacco Carcinogen ◽

Igf I ◽

The Impact ◽

Igfbp 3

The IGF axis has been implicated in the risk of various cancers. We previously reported a potential role of tissue-derived IGF in lung tumor formation and progression. However, the role of IGF-binding protein (IGFBP)-3, a major IGFBP, on the activity of tissue-driven IGF in lung cancer development is largely unknown. Here, we show that IGF-I, but not IGF-II, protein levels in non-small-cell lung cancer (NSCLC) were significantly higher than those in normal and hyperplastic bronchial epithelium. We found that IGF-I and IGFBP-3 levels in NSCLC tissue specimens were significantly correlated with phosphorylated IGF-IR (pIGF-IR) expression. We investigated the impact of IGFBP-3 expression on the activity of tissue-driven IGF-I in lung cancer development using mice carrying lung-specific human IGF-I transgene (Tg), a germline-null mutation of IGFBP-3, or both. Compared with wild-type (BP3+/+) mice, mice carrying heterozygous (BP3+/−) or homozygous (BP3−/−) deletion of IGFBP-3 alleles exhibited decreases in circulating IGFBP-3 and IGF-I. Unexpectedly, IGFTg mice with 50% of physiological IGFBP-3 (BP3+/−; IGFTg) showed higher levels of pIGF-IR/IR and a greater degree of spontaneous or tobacco carcinogen [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]-induced lung tumor development and progression than did the IGFTg mice with normal (BP3+/+;IGFTg) or homozygous deletion of IGFBP-3 (BP3−/−; IGFTg). These data show that IGF-I is overexpressed in NSCLC, leading to activation of IGF-IR, and that IGFBP-3, depending on its expression level, either inhibits or potentiates IGF-I actions in lung carcinogenesis.

Download Full-text

Immunology of Solid Tumors Beyond Tumor-Infiltrating Lymphocytes: The Role of Tertiary Lymphoid Structures

Biomarkers of the Tumor Microenvironment ◽

10.1007/978-3-319-39147-2_11 ◽

2017 ◽

pp. 259-280

Author(s):

Gert G. G. M. Van den Eynden ◽

Roberto Salgado ◽

Karen Willard-Gallo

Keyword(s):

Solid Tumors ◽

Tumor Infiltrating Lymphocytes ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures ◽

Infiltrating Lymphocytes

Download Full-text

Tertiary Lymphoid Structures as a Predictive Biomarker of Response to Cancer Immunotherapies

Frontiers in Immunology ◽

10.3389/fimmu.2021.674565 ◽

2021 ◽

Vol 12 ◽

Author(s):

Marta Trüb ◽

Alfred Zippelius

Keyword(s):

T Cells ◽

B Cells ◽

B Cell ◽

Tumour Response ◽

Predictive Biomarker ◽

Exciting Field ◽

Inflammatory Conditions ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures ◽

Cancer Immunotherapies

Tertiary lymphoid structures (TLS) are ectopic lymphoid formations which are formed under long-lasting inflammatory conditions, including tumours. TLS are composed predominantly of B cells, T cells and dendritic cells, and display various levels of organisation, from locally concentrated aggregates of immune cells, through clearly defined B cell follicles to mature follicles containing germinal centres. Their presence has been strongly associated with improved survival and clinical outcome upon cancer immunotherapies for patients with solid tumours, indicating potential for TLS to be used as a prognostic and predictive factor. Although signals involved in TLS generation and main cellular components of TLS have been extensively characterised, the exact mechanism by which TLS contribute to the anti-tumour response remain unclear. Here, we summarise the most recent development in our understanding of their role in cancer and in particular in the response to cancer immunotherapy. Deciphering the relationship between B cells and T cells found in TLS is a highly exciting field of investigation, with the potential to lead to novel, B-cell focused immunotherapies.

Download Full-text