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IgG4 subclass antibodies impair antitumor immunity in melanoma

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IgG4 subclass antibodies impair antitumor immunity in melanoma. / Karagiannis, Panagiotis; Gilbert, Amy E; Josephs, Debra H; Ali, Niwa; Dodev, Tihomir; Saul, Louise; Correa, Isabel; Roberts, Luke; Beddowes, Emma; Koers, Alexander; Hobbs, Carl; Ferreira, Silvia; Geh, Jenny L C; Healy, Ciaran; Harries, Mark; Acland, Katharine M; Blower, Philip J; Mitchell, Tracey; Fear, David J; Spicer, James F; Lacy, Katie E; Nestle, Frank O; Karagiannis, Sophia N.

In: J CLIN INVEST, Vol. 123, No. 4, 04.2013, p. 1457-74.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Karagiannis, P, Gilbert, AE, Josephs, DH, Ali, N, Dodev, T, Saul, L, Correa, I, Roberts, L, Beddowes, E, Koers, A, Hobbs, C, Ferreira, S, Geh, JLC, Healy, C, Harries, M, Acland, KM, Blower, PJ, Mitchell, T, Fear, DJ, Spicer, JF, Lacy, KE, Nestle, FO & Karagiannis, SN 2013, 'IgG4 subclass antibodies impair antitumor immunity in melanoma', J CLIN INVEST, vol. 123, no. 4, pp. 1457-74. https://doi.org/10.1172/JCI65579

APA

Karagiannis, P., Gilbert, A. E., Josephs, D. H., Ali, N., Dodev, T., Saul, L., Correa, I., Roberts, L., Beddowes, E., Koers, A., Hobbs, C., Ferreira, S., Geh, J. L. C., Healy, C., Harries, M., Acland, K. M., Blower, P. J., Mitchell, T., Fear, D. J., ... Karagiannis, S. N. (2013). IgG4 subclass antibodies impair antitumor immunity in melanoma. J CLIN INVEST, 123(4), 1457-74. https://doi.org/10.1172/JCI65579

Vancouver

Karagiannis P, Gilbert AE, Josephs DH, Ali N, Dodev T, Saul L et al. IgG4 subclass antibodies impair antitumor immunity in melanoma. J CLIN INVEST. 2013 Apr;123(4):1457-74. https://doi.org/10.1172/JCI65579

Bibtex

@article{51d7b505ca2f4b08b3b4ca6c709448ad,
title = "IgG4 subclass antibodies impair antitumor immunity in melanoma",
abstract = "Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10-driven Th2 immune responses in some inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. Consistent with Th2 inflammation, CD22+ B cells and IgG4(+)-infiltrating cells accumulated in tumors, and IL-10, IL-4, and tumor-reactive IgG4 were expressed in situ. When compared with B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Secreted B cells increased VEGF and IgG4, and tumor cells enhanced IL-10 secretion in cocultures. Unlike IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell-mediated tumor killing in vitro. Antigen-specific and nonspecific IgG4 inhibited IgG1-mediated tumoricidal functions. IgG4 blockade was mediated through reduction of FcγRI activation. Additionally, IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. Furthermore, serum IgG4 was inversely correlated with patient survival. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions against tumors, providing a previously unexplored aspect of tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches.",
keywords = "Adult, Aged, Aged, 80 and over, Animals, Antibody-Dependent Cell Cytotoxicity, Antineoplastic Agents/pharmacology, B-Lymphocytes/immunology, Cell Polarity, Coculture Techniques, Female, Forkhead Transcription Factors/metabolism, Humans, Immunoglobulin G/biosynthesis, Interleukin-10/metabolism, Interleukin-4/metabolism, Kaplan-Meier Estimate, Lymphatic Metastasis, Male, Melanoma/blood, Mice, Middle Aged, Receptors, IgG/metabolism, Sialic Acid Binding Ig-like Lectin 2/metabolism, Skin Neoplasms/blood, Th2 Cells/immunology, Tumor Cells, Cultured, Tumor Escape, Vascular Endothelial Growth Factor A/metabolism, Xenograft Model Antitumor Assays",
author = "Panagiotis Karagiannis and Gilbert, {Amy E} and Josephs, {Debra H} and Niwa Ali and Tihomir Dodev and Louise Saul and Isabel Correa and Luke Roberts and Emma Beddowes and Alexander Koers and Carl Hobbs and Silvia Ferreira and Geh, {Jenny L C} and Ciaran Healy and Mark Harries and Acland, {Katharine M} and Blower, {Philip J} and Tracey Mitchell and Fear, {David J} and Spicer, {James F} and Lacy, {Katie E} and Nestle, {Frank O} and Karagiannis, {Sophia N}",
year = "2013",
month = apr,
doi = "10.1172/JCI65579",
language = "English",
volume = "123",
pages = "1457--74",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "4",

}

RIS

TY - JOUR

T1 - IgG4 subclass antibodies impair antitumor immunity in melanoma

AU - Karagiannis, Panagiotis

AU - Gilbert, Amy E

AU - Josephs, Debra H

AU - Ali, Niwa

AU - Dodev, Tihomir

AU - Saul, Louise

AU - Correa, Isabel

AU - Roberts, Luke

AU - Beddowes, Emma

AU - Koers, Alexander

AU - Hobbs, Carl

AU - Ferreira, Silvia

AU - Geh, Jenny L C

AU - Healy, Ciaran

AU - Harries, Mark

AU - Acland, Katharine M

AU - Blower, Philip J

AU - Mitchell, Tracey

AU - Fear, David J

AU - Spicer, James F

AU - Lacy, Katie E

AU - Nestle, Frank O

AU - Karagiannis, Sophia N

PY - 2013/4

Y1 - 2013/4

N2 - Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10-driven Th2 immune responses in some inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. Consistent with Th2 inflammation, CD22+ B cells and IgG4(+)-infiltrating cells accumulated in tumors, and IL-10, IL-4, and tumor-reactive IgG4 were expressed in situ. When compared with B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Secreted B cells increased VEGF and IgG4, and tumor cells enhanced IL-10 secretion in cocultures. Unlike IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell-mediated tumor killing in vitro. Antigen-specific and nonspecific IgG4 inhibited IgG1-mediated tumoricidal functions. IgG4 blockade was mediated through reduction of FcγRI activation. Additionally, IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. Furthermore, serum IgG4 was inversely correlated with patient survival. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions against tumors, providing a previously unexplored aspect of tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches.

AB - Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10-driven Th2 immune responses in some inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. Consistent with Th2 inflammation, CD22+ B cells and IgG4(+)-infiltrating cells accumulated in tumors, and IL-10, IL-4, and tumor-reactive IgG4 were expressed in situ. When compared with B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Secreted B cells increased VEGF and IgG4, and tumor cells enhanced IL-10 secretion in cocultures. Unlike IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell-mediated tumor killing in vitro. Antigen-specific and nonspecific IgG4 inhibited IgG1-mediated tumoricidal functions. IgG4 blockade was mediated through reduction of FcγRI activation. Additionally, IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. Furthermore, serum IgG4 was inversely correlated with patient survival. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions against tumors, providing a previously unexplored aspect of tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Animals

KW - Antibody-Dependent Cell Cytotoxicity

KW - Antineoplastic Agents/pharmacology

KW - B-Lymphocytes/immunology

KW - Cell Polarity

KW - Coculture Techniques

KW - Female

KW - Forkhead Transcription Factors/metabolism

KW - Humans

KW - Immunoglobulin G/biosynthesis

KW - Interleukin-10/metabolism

KW - Interleukin-4/metabolism

KW - Kaplan-Meier Estimate

KW - Lymphatic Metastasis

KW - Male

KW - Melanoma/blood

KW - Mice

KW - Middle Aged

KW - Receptors, IgG/metabolism

KW - Sialic Acid Binding Ig-like Lectin 2/metabolism

KW - Skin Neoplasms/blood

KW - Th2 Cells/immunology

KW - Tumor Cells, Cultured

KW - Tumor Escape

KW - Vascular Endothelial Growth Factor A/metabolism

KW - Xenograft Model Antitumor Assays

U2 - 10.1172/JCI65579

DO - 10.1172/JCI65579

M3 - SCORING: Journal article

C2 - 23454746

VL - 123

SP - 1457

EP - 1474

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 4

ER -