Antigen-Driven Oligoclonal Expansion of Tumor-Infiltrating B Cells in Infiltrating Ductal Carcinoma of the Breast

Coronella, Julia; Spier, Catherine; Welch, Matthew; Trevor, Katrina T.; Stopeck, Alison; Villar, Hugo O.; Hersh, Evan M.

doi:10.4049/jimmunol.169.4.1829

Cited by 154 publications

(142 citation statements)

References 40 publications

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“…Restricted Ig gene expression in TIL-Bs has been described by others (36,37). Some investigators have suggested that this expansion occurs within the tumor tissue and in tumor-associated germinal centers (36). By contrast, our result shed light to another option where a tumor-draining LN could be the origin of the B cell response in our study.…”

Section: Discussioncontrasting

confidence: 55%

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Multiplex B Cell Characterization in Blood, Lymph Nodes, and Tumors from Patients with Malignancies

Zirakzadeh

Marits

Sherif

et al. 2013

The Journal of Immunology

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B lymphocytes contribute to immune surveillance, by tumor-specific Abs and Ag presentation to T lymphocytes, but are insufficiently studied in humans. In this article, we report a flow cytometric investigation of B lymphocyte subpopulations in blood, lymph nodes (LNs), and malignant tissues from 20 patients operated on because of advanced solid tumors. The CD19+ compartment in peripheral blood was essentially unaltered in patients, as compared with healthy control subjects. In metastatic LNs, signs of B lymphocyte activation were observed, as evidenced by increased proportions of plasmablasts and CD86-expressing cells. In tumor-infiltrating B lymphocytes (TIL-B), both switched memory cells and plasmablasts were expanded, as compared with nonmalignant epithelium. Moreover, pronounced skewing of Igλ/Igκ ratio was evident among TIL-Bs. By spectratype analysis on IgH, we confirmed a monoclonal expansion of the Vh7 family in TIL-B, also present in a tumor-associated LN. Sequencing the clonally expanded Vh7 revealed signs of somatic hypermutation. In conclusion, B lymphocytes in cancer patients exhibit signs of activation in tumor-associated tissues, likely induced by recognition of tumor Ags. Increased numbers of switched memory cells and plasmablasts in combination with clonal expansion and signs of somatic hypermutation suggest a CD4+ T lymphocyte–dependent antitumoral response, which may be exploited for immunotherapy.

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Section: Discussioncontrasting

confidence: 55%

“…8). Restricted Ig gene expression in TIL-Bs has been described by others (36,37). Some investigators have suggested that this expansion occurs within the tumor tissue and in tumor-associated germinal centers (36).…”

Section: Discussionmentioning

confidence: 99%

Multiplex B Cell Characterization in Blood, Lymph Nodes, and Tumors from Patients with Malignancies

Zirakzadeh

Marits

Sherif

et al. 2013

The Journal of Immunology

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“…It has also been reported that the infiltrating B cells in different types of cancers are clonal and express immunoglobulins that originate from a dominant germ line gene (47)(48)(49). Here, a tumor antigen, as opposed to a transplantation antigen, may drive the infiltrating cells and possibly tumor-specific mechanisms of local "immunosuppression" are also operant.…”

Section: Discussionmentioning

confidence: 99%

Ectopic B-cell clusters that infiltrate transplanted human kidneys are clonal

Cheng

Torkamani²,

Grover³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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B cells and their immunoglobulin products participate in allograft rejection of transplanted human kidneys in which an interesting feature is the presence of a germinal center like B-cell clusters in the allograft. We report here that the immunoglobulin repertoires of these infiltrating B cells are highly restricted and the B cells within a cluster are clonal. Antibody libraries made from the infiltrating B cells of individual patients unexpectedly revealed that each patient utilizes a particular set of dominant germ line genes as well as dominant complementarity determining region 3. Comparison of kidney and peripheral blood from the same patient showed that the immunoglobulin genes from both compartments had dominant clones, but they differed. The lymphocytes that infiltrate the kidneys express the immunoglobulin gene somatic recombination machinery usually restricted to highly activated lymphocytes in germinal centers and lymphomas. An analogy can be made between the inescapable antigenic drive in chronic infection versus that in an allograft, both of which may lead to emergence of dominant B-cell clones and even lymphoid malignancy.

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“…It has been proposed that the improved clinical outcome is due at least in part to the presence of prominent lymphocyte infiltrates in the tumor. [7][8][9][10][11] In contrast, invasive micropapillary carcinoma has a high incidence of axillary lymph node metastasis and poor prognosis and the mechanism is still poorly understood. In our previous study, 4 we found that invasive micropapillary carcinoma rich in tumor infiltrating lymphocytes was associated with an increased incidence of lymph node metastasis and an increased number of positive lymph nodes per case.…”

Section: Discussionmentioning

confidence: 99%

Tumor infiltrating lymphocytes differ in invasive micropapillary carcinoma and medullary carcinoma of breast

et al. 2008

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Tumor infiltrating lymphocytes have been correlated with a better prognosis for some tumors and medullary carcinoma of breast is a good example. However, in a recent study of invasive micropapillary carcinoma of breast, tumor infiltrating lymphocytes were associated with increased lymph node metastasis and a poorer prognosis. To explore possible mechanisms underlying this difference in immune responsiveness and tumor behavior, 28 cases of invasive micropapillary carcinoma with prominent lymphocyte infiltration were compared with 29 cases of medullary carcinoma. In both tumors, the majority of tumor infiltrating lymphocytes were T lymphocytes (Po0.01) with CD8 þ T lymphocytes predominant (Po0.01). Significantly, functional differences in CD8 þ cytotoxic T lymphocytes were identified in the two types of tumor. While lymphocytes infiltrated both the stroma and epithelial components of medullary carcinoma, the tumor infiltrating lymphocytes of invasive micropapillary carcinoma were almost exclusively confined to the stroma. Tumor infiltrating lymphocytes of medullary carcinoma showed stronger expression of FasL than those in invasive micropapillary carcinoma (Po0.01) and medullary carcinoma cells exhibited stronger expression of Fas than invasive micropapillary carcinoma cells did (Po0.01). In the subgroups of tumors with strong ( þ þ / þ þ þ ) Fas expression, double immunohistochemistry revealed that most of the tumor infiltrating lymphocytes in medullary carcinoma, particularly those infiltrating the tumor nests, were CD8 þ cytotoxic T lymphocytes, but not so in invasive micropapillary carcinoma. Furthermore, upregulated expression of perforin, granzyme B and FasL by cytotoxic T lymphocytes was greater in medullary carcinoma than invasive micropapillary carcinoma (Po0.01, respectively). The results suggest that effective immunity provided by tumor infiltrating lymphocytes varies in different tumors and the relative lack of tumor-killing cytotoxic T lymphocytes in invasive micropapillary carcinoma may explain, in part, the adverse association of tumor infiltrating lymphocytes with the biological behavior of invasive micropapillary carcinoma of breast. Modern Pathology (2008Pathology ( ) 21, 1101Pathology ( -1107 doi:10.1038/modpathol.2008 published online 9 May 2008 Keywords: tumor infiltrating lymphocytes; invasive micropapillary carcinoma; medullary carcinoma; breast; laser scanning confocal microscope Local and systemic inflammatory responses play an important role in the progression of a variety of common solid tumors. Tumor infiltrating lymphocytes are believed to represent the local immune response, a key mechanism in controlling tumor growth and metastasis, and an independent prognostic indicator for many tumors.1,2 This is well demonstrated in medullary carcinoma of breast which is characterized by large sheets of poorly differentiated tumor cells and a prominent lymphoplasmacytic infiltrate, rare lymph node metastasis and a good prognosis. 3 Invasive micropapillary carcinoma of breast is composed of sma...

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Antigen-Driven Oligoclonal Expansion of Tumor-Infiltrating B Cells in Infiltrating Ductal Carcinoma of the Breast

Cited by 154 publications

References 40 publications

Multiplex B Cell Characterization in Blood, Lymph Nodes, and Tumors from Patients with Malignancies

Multiplex B Cell Characterization in Blood, Lymph Nodes, and Tumors from Patients with Malignancies

Ectopic B-cell clusters that infiltrate transplanted human kidneys are clonal

Tumor infiltrating lymphocytes differ in invasive micropapillary carcinoma and medullary carcinoma of breast

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