Identification of tumor-reactive B cells and systemic IgG in breast cancer based on clonal frequency in the sentinel lymph node

McDaniel, Jonathan R.; Pero, Stephanie C.; Voss, William N.; Shukla, Girja S.; Sun, Yujing; Schaetzle, Sebastian; Lee, Chang Han; Horton, Andrew P.; Harlow, Seth P.; Gollihar, Jimmy; Ellefson, Jared W.; Krag, Christopher C.; Tanno, Yuri; Sidiropoulos, Nikoletta; Georgiou, George; Ippolito, Gregory C.; Krag, David N.

doi:10.1007/s00262-018-2123-2

Cited by 33 publications

(22 citation statements)

References 43 publications

(49 reference statements)

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“…The opposite was also true, the presence of given autoantibodies in the circulation was not indicative of the autoantibody production in situ . Whether such B cells were activated in draining lymph nodes as it has been recently demonstrated for anti-CTAG1B B cells in BC patients ( 39 ) and never infiltrated the tumors or whether they were activated in BC-associated TLS but left the tissue is not known.…”

Section: Discussionmentioning

confidence: 95%

Antigen Specificity and Clinical Significance of IgG and IgA Autoantibodies Produced in situ by Tumor-Infiltrating B Cells in Breast Cancer

et al. 2018

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An important role for tumor infiltrating B lymphocytes (TIL-B) in the immune response to cancer is emerging; however, very little is known about the antigen specificity of antibodies produced in situ. The presence of IgA antibodies in the tumor microenvironment has been noted although their biological functions and clinical significance are unknown. This study used a 91-antigen microarray to examine the IgG and IgA autoantibody repertoires in breast cancer (BC). Tumor and adjacent breast tissue supernatants and plasma from BC patients together with normal breast tissue supernatants and plasma from healthy controls (patients undergoing mammary reduction and healthy blood donors) were analyzed to investigate relationships between autoantibodies and the clinical, histological and immunological features of tumors. Our data show that >84% of the BC samples tested contain autoantibodies to one or more antigens on the array, with ANKRD30BL, COPS4, and CTAG1B being most frequently reactive. Ex vivo TIL-B responses were uncoupled from systemic humoral responses in the majority of cases. A comparison of autoantibody frequencies in supernatants and plasma from patients and controls identified eight antigens that elicit BC-associated autoantibody responses. The overall prevalence of IgG and IgA autoantibodies was similar and while IgG and IgA responses were not linked they did correlate with distinct clinical, pathological and immunological features. Higher levels of ex vivo IgG responses to BC-associated antigens were associated with shorter recurrence-free survival (RFS), HER2 overexpression and lower tumor-infiltrating CD8+ T cell counts. Higher IgA levels were associated with estrogen and progesterone receptor-negative cancers but were not significantly associated with RFS. Furthermore, ex vivo IgA but not IgG autoantibodies reactive to BC-associated antigens were linked with germinal center and early memory B cell maturation and the presence of tertiary lymphoid structures suggesting that these TIL-B are activated in the tumor microenvironment. Overall, our results extend the current understanding of the antigen specificity, the biological and the clinical significance of IgG and IgA autoantibodies produced by BC TIL-B in situ.

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Section: Discussionmentioning

confidence: 95%

Antigen Specificity and Clinical Significance of IgG and IgA Autoantibodies Produced in situ by Tumor-Infiltrating B Cells in Breast Cancer

et al. 2018

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“…Studies have shown that antigen-driven B cells migrate into the breast tumor microenvironment, proliferate, undergo somatic hypermutation and affinity maturation. 22 – 24 However, it is unclear as to the extent of this B cell activity in patients that have recurrences, distant metastasis, or poor disease-free and overall survival. Therefore, follow-up studies to test the function of B cells from breast cancer patients are required for better characterization of B cells in these patients.…”

Section: Discussionmentioning

confidence: 99%

Sentinel lymph node B cells can predict disease-free survival in breast cancer patients

Blenman

Frankel

et al. 2018

npj Breast Cancer

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Tumor invasion into draining lymph nodes, especially sentinel lymph nodes (SLNs), is a key determinant of prognosis and treatment in breast cancer as part of the TNM staging system. Using multicolor histology and quantitative image analysis, we quantified immune cells within SLNs from a discovery cohort of 76 breast cancer patients. We found statistically more in situ CD3+ T cells in tumor negative vs. tumor positive nodes (mean of 8878 vs. 6704, respectively, p = 0.006), but no statistical difference in CD20+ B cells or CD1a+ dendritic cells. In univariate analysis, a reduced hazard was seen with a unit increase in log CD3 with HR 0.49 (95% CI 0.30–0.80) and log CD20 with HR 0.37 (95% CI 0.22–0.62). In multivariate analysis, log CD20 remained significant with HR 0.42 (95% CI 0.25–0.69). When restricted to SLN tumor negative patients, increased log CD20 was still associated with improved DFS (HR = 0.26, 95% CI 0.08–0.90). The CD20 results were validated in a separate cohort of 21 patients (n = 11 good outcome, n = 10 poor outcome) with SLN negative triple-negative breast cancer (TNBC) (“good” mean of 7011 vs. “poor” mean of 4656, p = 0.002). Our study demonstrates that analysis of immune cells within SLNs, regardless of tumor invasion status, may provide additional prognostic information, and highlights B cells within SLNs as important in preventing future recurrence.

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“…A trend toward improved 5-year survival was noted in melanoma patients, whose SLNs demonstrated follicular hyperplasia/GC accumulation ( 88 ). Besides their prognostic value for disease-free survival in breast cancer patients ( 89 ), SLN B cells is the source of affinity matured B cell clones that produced anti-tumor immunoglobulins detected in the blood ( 90 ). Investigation of such antibodies could potentially lead to the recognition of tumor antigens recognized by the immune system, which can subsequently be targeted in the context of immunotherapies ( 90 ).…”

Section: Lymph Nodes In Neoplasmsmentioning

confidence: 99%

“…Besides their prognostic value for disease-free survival in breast cancer patients ( 89 ), SLN B cells is the source of affinity matured B cell clones that produced anti-tumor immunoglobulins detected in the blood ( 90 ). Investigation of such antibodies could potentially lead to the recognition of tumor antigens recognized by the immune system, which can subsequently be targeted in the context of immunotherapies ( 90 ). Furthermore, these findings imply that development of tumor-specific Tfh cells could be a critical factor for an effector response to a tumor.…”

Section: Lymph Nodes In Neoplasmsmentioning

confidence: 99%

Lymph Node Cellular Dynamics in Cancer and HIV: What Can We Learn for the Follicular CD4 (Tfh) Cells?

Poultsidi

Dimopoulos²,

et al. 2018

Front. Immunol.

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Lymph nodes (LNs) are central in the generation of adaptive immune responses. Follicular helper CD4 T (Tfh) cells, a highly differentiated CD4 population, provide critical help for the development of antigen-specific B cell responses within the germinal center. Throughout the past decade, numerous studies have revealed the important role of Tfh cells in Human Immunodeficiency Virus (HIV) pathogenesis as well as in the development of neutralizing antibodies post-infection and post-vaccination. It has also been established that tumors influence various immune cell subsets not only in their proximity, but also in draining lymph nodes. The role of local or tumor associated lymph node Tfh cells in disease progression is emerging. Comparative studies of Tfh cells in chronic infections and cancer could therefore provide novel information with regards to their differentiation plasticity and to the mechanisms regulating their development.

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Identification of tumor-reactive B cells and systemic IgG in breast cancer based on clonal frequency in the sentinel lymph node

Cited by 33 publications

References 43 publications

Antigen Specificity and Clinical Significance of IgG and IgA Autoantibodies Produced in situ by Tumor-Infiltrating B Cells in Breast Cancer

Antigen Specificity and Clinical Significance of IgG and IgA Autoantibodies Produced in situ by Tumor-Infiltrating B Cells in Breast Cancer

Sentinel lymph node B cells can predict disease-free survival in breast cancer patients

Lymph Node Cellular Dynamics in Cancer and HIV: What Can We Learn for the Follicular CD4 (Tfh) Cells?

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