EpCAM, a human tumor-associated antigen promotes Th2 development and tumor immune evasion

Ziegler, Alexandra I.; Heidenreich, Regina; Braumüller, Heidi; Wolburg, Hartwig; Weidemann, Susanne; Mocikat, Ralph; Röcken, Martin

doi:10.1182/blood-2008-08-175109

Cited by 67 publications

(57 citation statements)

References 48 publications

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“…We identified Il4 as a transcriptional target of Hh signaling in T cells, and this is of interest not only because of its pivotal role in Th2 biology, but also because of the function of IL-4 in signaling to other immune cells. Increased IL-4 in tumor microenvironments can inhibit antitumor responses or promote tumor growth (45,46). Of interest, increased IL-4 has been observed in several cancers strongly associated with aberrant Hh signaling (47)(48)(49), and IL-4 derived from tumor-resident T cells sustained growth of follicular B lymphomas (50), tumors known to produce Hh ligands (51).…”

Section: Discussionmentioning

confidence: 99%

Tissue-Derived Hedgehog Proteins Modulate Th Differentiation and Disease

Furmanski

Saldaña

Ono

et al. 2013

The Journal of Immunology

120

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Genome-wide association studies into complex immune-mediated diseases have indicated that many genetic factors, each with individual low risk, contribute to overall disease. It is therefore timely and important to characterise how immune responses may be subtly modified by tissue context. Here we explore the role of tissue-derived molecules in influencing the function of T-cells, which, due to their migratory nature, come into contact with many different microenvironments through their lifespan. Hedgehog (Hh) proteins act as secreted morphogens, providing concentration-dependent positional and temporal cell-fate specification in solid tissues. Hh signalling is required for embryogenesis and is important in postnatal tissue renewal and in malignancy. However, the function of Hh in dynamic, fluid systems such as in mammalian immunity is largely unknown. Here we show that Hh-dependent transcription in T-cells promoted Th2 transcriptional programs and differentiation, exacerbating allergic pathology. Interestingly, expression of Sonic Hedgehog (Shh) increased in lung epithelial cells following the induction of allergic disease, and lung T-cells upregulated Hh-target gene expression, indicating that T-cells respond to locally-secreted Hh ligands in vivo. We show that Il4, the key Th2 cytokine, is a novel transcriptional target of Hh signals in T-cells, providing one mechanism for the role of Hh in Th differentiation. We propose that Hh, secreted from inflamed, remodelling or malignant tissue can modulate local T-cell function. Our data present an unexpected and novel role for tissue-derived morphogens in the regulation of fluid immune responses, with implications for allergy and tumour responses, suggesting new uses for anti-Hh therapeutics.

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Section: Discussionmentioning

confidence: 99%

Tissue-Derived Hedgehog Proteins Modulate Th Differentiation and Disease

Furmanski

Saldaña

Ono

et al. 2013

The Journal of Immunology

120

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“…Thereby, trAbs recruit and activate different types of immune effector cells at the targeted tumor where they mediate effective tumor cell destruction (3). The interplay between T cells, tumor cells, and accessory cells mainly leads to the induction of a Th1 response, which is a prerequisite for potent tumor rejection (4,5). Furthermore, it has been shown that antigen-presenting cells recruited to the tumor site subsequently present the phagocytosed and processed tumor-associated antigens to T cells (2).…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Tolerability of a GD2-Directed Trifunctional Bispecific Antibody in a Preclinical Model: Subcutaneous Administration Is Superior to Intravenous Delivery

Deppisch

Rosenberger²,

Eißler

et al. 2015

Molecular Cancer Therapeutics

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Trifunctional bispecific antibodies (trAb) are novel anticancer drugs that recruit and activate different types of immune effector cells at the targeted tumor. Thus, tumor cells are effectively eliminated and a long-lasting tumor-specific T-cell memory is induced. The trAb Ektomab is directed against human CD3 on T cells and the tumor-associated ganglioside GD2, which is an attractive target for immunotherapy of melanoma in humans. To optimize clinical applicability, we studied different application routes with respect to therapeutic efficacy and tolerability by using the surrogate trAb Surek (anti-GD2 Â anti-murine CD3) and a murine melanoma engineered to express GD2. We show that subcutaneous injection of the trAb is superior to the intravenous delivery pathway, which is the standard application route for therapeutic antibodies. Despite lower plasma levels after subcutaneous administration, the same tumor-protective potential was observed in vivo compared with intravenous administration of Surek. However, subcutaneously delivered Surek showed better tolerability. This could be explained by a continuous release of the antibody leading to constant plasma levels and a delayed induction of proinflammatory cytokines. Importantly, the induction of counter-regulatory mechanisms was reduced after subcutaneous application. These findings are relevant for the clinical application of trifunctional bispecific antibodies and, possibly, also other immunoglobulin constructs.

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“…Moreover, the tumor antigens inducing the T cell response may also play an important part in deciding whether the immune response will promote or inhibit its progression. Ziegler et al in their study on colon cancer demonstrated strong promotion of Th2 type of response by tumor associated antigen EpCAM both invitro and invivo and hence tumor immune evasion [23]. The antigens which may be important for maintenance of CI equilibrium however remain to be identified.…”

Section: What Maintains the CI Equilibrium?mentioning

confidence: 99%

Cancer-Immune Equilibrium: Questions Unanswered

Bhatia

Kumar

2011

Cancer Microenvironment

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Cancer-immune (CI) equilibrium constitutes an important component of the cancer immunoediting theory. It is defined as a period during which our immune system and cancer live in harmony in the body. The immune system, though not able to completely eliminate the cancer, doesn't allow it to progress or metastasize further. Mechanisms of this phase are poorly understood because this phase is difficult to identify even by the most modern detection methods. Till now, the work done on the equilibrium phase of cancer, suggests promising improvements in cancer therapy if the disease could be withheld in this phase. However, there are many queries which remain to be addressed about this interesting yet unresolved phase of cancer immunity.

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EpCAM, a human tumor-associated antigen promotes Th2 development and tumor immune evasion

Abstract: Experimental tumor vaccination and adoptive T-cell therapies show that interferon-␥ (IFN-␥)-producing CD4

Cited by 67 publications

References 48 publications

Tissue-Derived Hedgehog Proteins Modulate Th Differentiation and Disease

Tissue-Derived Hedgehog Proteins Modulate Th Differentiation and Disease

Efficacy and Tolerability of a GD2-Directed Trifunctional Bispecific Antibody in a Preclinical Model: Subcutaneous Administration Is Superior to Intravenous Delivery

Cancer-Immune Equilibrium: Questions Unanswered

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