Functional Th1-oriented T follicular helper cells that infiltrate human breast cancer promote effective adaptive immunity

Noel, G. R.; Fontsa, Mireille Langouo; Garaud, Soizic; Silva, Pushpamali De; Wind, Alexandre de; Eynden, Gert G. Van den; Salgado, Roberto; Boisson, Anaïs; Locy, Hanne; Thomas, Noémie; Solinas, Cinzia; Migliori, Edoardo; Naveaux, Céline; Duvillier, Hugues; Lucas, Sophie; Craciun, Ligia; Thielemans, Kris; Larsimont, Denis; Willard-Gallo, Karen

doi:10.1172/jci139905

Cited by 97 publications

(87 citation statements)

References 63 publications

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“…Indeed, this method can be performed with RNA extracted from FFPE tissue used for TIL-IHC, can be automated and allows TIL scoring based on a diverse yet still comprehendible set of 770 genes. Moreover, the complementarity of nanoString nCounter ® gene expression analysis with immunohistochemistry has been shown while investigating immune gene profiles associated with breast cancer cohorts characterized by absence versus presence of nonactive or active TLS (36). Here, we observed that TIL-HE, TIL-CD3, and TIL-CD8 showed high correlation coefficients with TIL-NS, suggesting that variability in TIL-IHC could be resolved when complemented with TIL-NS.…”

Section: Discussionmentioning

confidence: 60%

Assessing Tumor-Infiltrating Lymphocytes in Breast Cancer: A Proposal for Combining Immunohistochemistry and Gene Expression Analysis to Refine Scoring

Locy

Verhulst²,

Cools

et al. 2022

Front. Immunol.

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Scoring of tumor-infiltrating lymphocytes (TILs) in breast cancer specimens has gained increasing attention, as TILs have prognostic and predictive value in HER2+ and triple-negative breast cancer. We evaluated the intra- and interrater variability when scoring TILs by visual inspection of hematoxylin and eosin-stained tissue sections. We further addressed whether immunohistochemical staining of these sections for immune cell surface markers CD45, CD3, CD4, and CD8 and combination with nanoString nCounter® gene expression analysis could refine TIL scoring. Formalin-fixed paraffin-embedded and fresh-frozen core needle biopsies of 12 female and treatment-naive breast cancer patients were included. Scoring of TILs was performed twice by three independent pathologists with a washout period of 3 days. Increasing intra- and interrater variability was observed with higher TIL numbers. The highest reproducibility was observed on tissue sections stained for CD3 and CD8. The latter TIL scores correlated well with the TIL scores obtained through nanoString nCounter® gene expression analysis. Gene expression analysis also revealed 104 and 62 genes that are positively and negatively related to both TIL scores. In conclusion, integration of immunohistochemistry and gene expression analysis is a valuable strategy to refine TIL scoring in breast tumors.

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Section: Discussionmentioning

confidence: 60%

Assessing Tumor-Infiltrating Lymphocytes in Breast Cancer: A Proposal for Combining Immunohistochemistry and Gene Expression Analysis to Refine Scoring

Locy

Verhulst²,

Cools

et al. 2022

Front. Immunol.

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“…The fifteen included studies were retrospective studies published between 2015 and 2021, with a patient population ranging from 60 to 769. Seven studies were performed in Korea ( 18 , 20 , 23 – 25 , 27 , 28 ), five in China ( 19 , 22 , 29 – 31 ), two in Greece ( 10 , 26 ), and one in Belgium ( 21 ). Ten of the 15 included studies reported the correlation between clinicopathological features and TLSs (TNM stage, 4 studies; age, 5 studies; tumor size, 4 studies; lymph node status, 7 studies; LVI, 4 studies; histological grade, 7 studies; TILs, 3 studies; ER, 3 studies; PR, 3 studies; HER-2, 6 studies; Ki-67, 2 studies).…”

Section: Resultsmentioning

confidence: 99%

The Presence of Tertiary Lymphoid Structures Provides New Insight Into the Clinicopathological Features and Prognosis of Patients With Breast Cancer

et al. 2022

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BackgroundTertiary lymphoid structures (TLSs) have been proven to be predictive biomarkers of favorable clinical outcomes and response to immunotherapies in several solid malignancies. Nevertheless, the effect of TLSs in patients with breast cancer (BC) remains controversial. The objective of the current study is to investigate the clinicopathological and prognostic significance of TLSs in BC. Given the unique difficulties for detecting and quantifying TLSs, a TLS-associated gene signature based on The Cancer Genome Atlas (TCGA) BC cohort was used to validate and supplement our results.MethodsElectronic platforms (PubMed, Web of Science, EMBASE, the Cochrane Library, CNKI, and Wanfang) were searched systematically to identify relevant studies as of January 11, 2022. We calculated combined odds ratios (ORs) with 95% confidence intervals (CIs) to determine the relationship between clinicopathological parameters and TLSs. The pooled hazard ratios (HRs) and 95% CIs were also calculated to evaluate the prognostic significance of TLSs. The TLS signature based on the TCGA BC cohort was applied to validate and supplement our results.ResultsFifteen studies with 3,898 patients were eligible for enrollment in our study. The combined analysis indicated that the presence of TLSs was related to improved disease-free survival (DFS) (HR = 0.61, 95% CI: 0.41–0.90, p < 0.05) and overall survival (OS) (HR = 1.66, 95% CI: 1.26–2.20, p < 0.001). Additionally, the presence of TLSs was positively correlated with early tumor TNM stage and high tumor-infiltrating lymphocytes. TLS presence was positively related to human epidermal growth factor receptor 2 (HER-2) and Ki-67 but inversely correlated with the status of estrogen and progesterone receptor. Simultaneously, our study found that tumor immune microenvironment was more favorable in the high-TLS signature group than in the low-TLS signature group. Consistently, BC patients in the high-TLS signature group exhibited better survival outcomes compared to those in the low-TLS signature group, suggesting that TLSs might be favorable prognostic biomarkers.ConclusionsTLS presence provides new insight into the clinicopathological features and prognosis of patients with BC, whereas the factors discussed limited the evidence quality of this study. We look forward to consistent methods to define and characterize TLSs, and more high-quality prospective clinical trials designed to validate the value of TLSs alone or in combination with other markers.

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“…The balance of T FH /Th1 differentiation from precursor cells is determined by the competitive expression of Bcl6 and T-bet [ 71 , 89 , 90 , 91 ]. Further investigation revealed that tumor-infiltrating T FH cells produce CXCL13 to attract CXCR5 + CD8 + T cells and CXCR5 + B cells toward the germinal centers within the TLS, where both T cells and B cells are primed, reinforcing their cytotoxic capacity against cancer cells [ 92 ]. These studies indicate that BCL6-dominant signaling promotes CXCL13 expression in T FH cells [ 93 ].…”

Section: The Expression and Implications Of Cxcl13/cxcr5mentioning

confidence: 99%

Potential Role of CXCL13/CXCR5 Signaling in Immune Checkpoint Inhibitor Treatment in Cancer

Hsieh

Jian

Lin

et al. 2022

Cancers

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Immune checkpoint inhibitors (ICIs), including antibodies that target programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA4), represent some of the most important breakthroughs in new drug development for oncology therapy from the past decade. CXC chemokine ligand 13 (CXCL13) exclusively binds CXC chemokine receptor type 5 (CXCR5), which plays a critical role in immune cell recruitment and activation and the regulation of the adaptive immune response. CXCL13 is a key molecular determinant of the formation of tertiary lymphoid structures (TLSs), which are organized aggregates of T, B, and dendritic cells that participate in the adaptive antitumor immune response. CXCL13 may also serve as a prognostic and predictive factor, and the role played by CXCL13 in some ICI-responsive tumor types has gained intense interest. This review discusses how CXCL13/CXCR5 signaling modulates cancer and immune cells to promote lymphocyte infiltration, activation by tumor antigens, and differentiation to increase the antitumor immune response. We also summarize recent preclinical and clinical evidence regarding the ICI-therapeutic implications of targeting the CXCL13/CXCR5 axis and discuss the potential role of this signaling pathway in cancer immunotherapy.

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Functional Th1-oriented T follicular helper cells that infiltrate human breast cancer promote effective adaptive immunity

Cited by 97 publications

References 63 publications

Assessing Tumor-Infiltrating Lymphocytes in Breast Cancer: A Proposal for Combining Immunohistochemistry and Gene Expression Analysis to Refine Scoring

Assessing Tumor-Infiltrating Lymphocytes in Breast Cancer: A Proposal for Combining Immunohistochemistry and Gene Expression Analysis to Refine Scoring

The Presence of Tertiary Lymphoid Structures Provides New Insight Into the Clinicopathological Features and Prognosis of Patients With Breast Cancer

Potential Role of CXCL13/CXCR5 Signaling in Immune Checkpoint Inhibitor Treatment in Cancer

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