IgG4 subclass antibodies impair antitumor immunity in melanoma

Karagiannis, Panagiotis; Gilbert, Amy E.; Josephs, Debra H.; Ali, Nasreen; Dodev, Tihomir; Saul, Louise; Correa, Isabel; Roberts, Luke B.; Beddowes, Emma; Koers, Alex; Hobbs, Carl; Ferreira, Sandra Reis; Geh, Jenny; Healy, Ciaran; Harries, Mark; Acland, K.; Blower, Philip J.; Mitchell, Tracey; Fear, David; Spicer, James; Lacy, Katie E.; Nestle, Frank O.; Karagiannis, Sophia N.

doi:10.1172/jci65579

Cited by 174 publications

(210 citation statements)

References 73 publications

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“…79 This report is in agreement with evidence for the presence of IgG4 antibody+ B cells in pancreatic cancer, extrahepatic cholangiocarcinoma and squamous cell carcinoma, providing evidence that this phenomenon of IgG4 impairment of the immune response in the tumor microenvironment may not be limited to melanoma. 125,126 Increased production of Th2 cytokines such as IL-4 and IL-10, has been described in the tumor microenvironment of melanoma and other cancers; [127][128][129] and IgG4, rather than IgE antibodies have been described to be elevated in individuals chronically exposed to known allergic triggers such as bee venom and animal fur.…”

Section: Ige An Antibody Class Less Prone To Tumor-induced Antibodysupporting

confidence: 90%

“…78 It is possible that these findings are due to either induction of class switching to IgE in Th2-biased milieu within the tumor microenvironment and may be indicative of a redirected, belated or inefficient immune response to cancer growth. 79,80 Nonetheless, these findings may suggest that IgE antibodies could also harbor tumor-eradicating functions. …”

Section: Allergooncology: Wielding the Allergic Response Against Cancermentioning

confidence: 99%

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IgE immunotherapy

Josephs

Spicer

Karagiannis

et al. 2013

mAbs

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Section: Ige An Antibody Class Less Prone To Tumor-induced Antibodysupporting

confidence: 90%

Section: Allergooncology: Wielding the Allergic Response Against Cancermentioning

confidence: 99%

IgE immunotherapy

Josephs

Spicer

Karagiannis

et al. 2013

mAbs

Self Cite

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“…In contrast, Env-specific CD4 + T cells demonstrated much stronger and more sustained Th2 cytokine expression as compared with Gag-specific CD4 + T cells, although Th1 cytokine responses were also evident. Intriguingly, the cytokines IL-4, IL-10, and IL-13 for which we observed enhanced secretion from Env-specific CD4 + T cells in mice are associated with the induction of the inhibitory IgG4 subclass in humans (48)(49)(50)(51)(52). Unfortunately, most Th2 responses of RV138 vaccinees were below the detection limit of our assays.…”

Section: Discussionmentioning

confidence: 66%

Enhancing the Quality of Antibodies to HIV-1 Envelope by GagPol-Specific Th Cells

Bonsmann

Niezold

Temchura

et al. 2015

The Journal of Immunology

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The importance of Fc-dependent effector functions of Abs induced by vaccination is increasingly recognized. However, vaccination of mice against HIV envelope (Env) induced a skewed Th cell response leading to Env-specific Abs with reduced effector function. To overcome this bias, GagPol-specific Th cells were harnessed to provide intrastructural help for Env-specific B cells after immunization with virus-like particles containing GagPol and Env. This led to a balanced Env-specific humoral immune response with a more inflammatory Fc glycan profile. The increased quality in the Ab response against Env was confirmed by FcγR activation assays. Because the Env-specific Th cell response was also biased in human vaccinees, intrastructural help is an attractive novel approach to increase the efficacy of prophylactic HIV Env-based vaccines and may also be applicable to other particulate vaccines.

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“…With regard to IgG, the IgG4 subclass has been linked to a worse outcome and has turned out to have blocking effects on the binding of tumor-specific IgG1. 36 On the other hand, the ectopic expression of FcγRIIB, an inhibitory receptor for IgG, on melanoma cells was found to promote liver metastasis allowing the tumor to escape humoral immunity. 15 Unexpectedly, a high proportion of PCs expressed IgA.…”

Section: Discussionmentioning

confidence: 99%

Plasma cells in primary melanoma. Prognostic significance and possible role of IgA

et al. 2016

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Melanoma is not only one of the most immunogenic cancers but also one of the most effective cancers at subverting host immunity. The role of T lymphocytes in tumor immunity has been extensively studied in melanoma, whereas less is known about the importance of B lymphocytes. The effects of plasma cells (PCs), in particular, are still obscure. The aim of this study was to characterize pathological features and clinical outcome of primary cutaneous melanomas associated with PCs. Moreover, we investigated the origins of the melanoma-associated PCs. Finally, we studied the outcome of patients with primary melanomas with PCs. We reviewed 710 melanomas to correlate the presence of PCs with histological prognostic markers. Immunohistochemistry for CD138 and heavy and light chains was performed in primary melanomas (PM) and in loco-regional lymph nodes (LN), both metastatic and not metastatic. In three PM and nine LN with frozen material, VDJ-rearrangement was analyzed by Gene Scan Analysis. Survival analysis was performed on a group of 85 primary melanomas 42 mm in thickness. Forty-one cases (3.7%) showed clusters/sheets of PCs. PC-rich melanomas occurred at an older age and were thicker, more often ulcerated and more mitotically active (Po 0.05). PCs were polyclonal and often expressed IgA in addition to IgG. In LN, clusters/sheets of IgA+ PCs were found both in the sinuses and subcapsular areas. Analysis of VDJ-rearrangements showed the IgA to be oligoclonal. Melanomas with clusters/sheets of PCs had a significantly worse survival compared with melanomas without PCs while, interestingly, melanomas with sparse PCs were associated with a better clinical outcome (P = 0.002). In conclusion, melanomas with sheets/clusters of PCs are associated with worse prognosis. IgG and IgA are the isotypes predominantly produced by these PCs. IgA oligoclonality suggests an antigen-driven response that facilitates melanoma progression by a hitherto unknown mechanism.

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IgG4 subclass antibodies impair antitumor immunity in melanoma

Cited by 174 publications

References 73 publications

IgE immunotherapy

IgE immunotherapy

Enhancing the Quality of Antibodies to HIV-1 Envelope by GagPol-Specific Th Cells

Plasma cells in primary melanoma. Prognostic significance and possible role of IgA

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