Cryptic Epitopes Induce High-Titer Humoral Immune Response in Patients with Cancer

Fischer, Eliane; Kobold, Sebastian; Kleber, Sascha; Kubuschok, Boris; Braziulis, Erik; Renner, Christoph; Wadle, Andreas

doi:10.4049/jimmunol.0902166

Cited by 11 publications

(7 citation statements)

References 47 publications

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“…This phenomenon was suggested to aid immune maturation and the formation of vaccines to enable the killing of tumor cells. It was shown that ingestion of blebs by mouse-derived dendritic cells induced their maturation and subsequent Th17 cell activation when co-cultured with splenocytes in vitro [ 138 , 139 ], as well as in mice in vivo [ 140 ]. Ruben et al [ 116 ] showed that blebs were generated from mitoxantrone-treated apoptotic HL60 cells (the human HLA-A2-negative AML cell line), which contain chromatin and endoplasmic reticulum.…”

Section: Role Of Blebbing In Cellular Locomotionmentioning

confidence: 99%

Involvement of Membrane Blebbing in Immunological Disorders and Cancer

Khajah¹,

Luqmani

2015

Med Princ Pract

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Cellular blebbing is a unique form of dynamic protrusion emanating from the plasma membrane which can be either apoptotic or nonapoptotic in nature. Blebs have been observed in a wide variety of cell types and in response to multiple mechanical and chemical stimuli. They have been linked to various physiological and pathological processes including tumor motility and invasion, as well as to various immunological disorders. They can form and retract extremely rapidly in seconds or minutes, or slowly over hours or days. This review focuses on recent evidence regarding the role of blebbing in cell locomotion with particular emphasis on its role in tumor metastasis, indicating the role of specific causative molecules. The phenomenon of blebbing has been observed in endocrine-resistant breast cancer cells in response to brief exposure to extracellular alkaline pH, which leads to enhanced invasive capacity. Genetic or pharmacological targeting of cellular blebs could serve as a potential therapeutic option to control tumor metastasis.

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Section: Role Of Blebbing In Cellular Locomotionmentioning

confidence: 99%

Involvement of Membrane Blebbing in Immunological Disorders and Cancer

Khajah¹,

Luqmani

2015

Med Princ Pract

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“…Some of the most common host-derived antibodies target Her2, p53, MUC1, and endostatin [53], and to date over 250 breast cancer antigens have been identified [35]. Non-identified antigens, also known as “cryptic epitopes”, which were discovered by sequencing V(D)J regions and not finding a matched antigen, have also been documented [51,54] and are specific for binding to breast cancer cells and not normal tissue [54]. Together, these data demonstrate that active, humoral immune responses do occur in at least some breast cancer patients although, these processes are not solely B cell dependent.…”

Section: Introductionmentioning

confidence: 99%

“…Serum antibodies to tumor-specific antigens have been documented in pancreatic, cervical, gastric and ovarian cancers [35,39,52,54,97]. Presence of antibodies to MUC1, a common tumor antigen, showed improved survival for ovarian, gastric, lung and pancreatic cancers [97].…”

Section: Introductionmentioning

confidence: 99%

Role of Tertiary Lymphoid Structures (TLS) in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

Pimenta

Barnes

2014

Cancers

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Following the successes of monoclonal antibody immunotherapies (trastuzumab (Herceptin®) and rituximab (Rituxan®)) and the first approved cancer vaccine, Provenge® (sipuleucel-T), investigations into the immune system and how it can be modified by a tumor has become an exciting and promising new field of cancer research. Dozens of clinical trials for new antibodies, cancer and adjuvant vaccines, and autologous T and dendritic cell transfers are ongoing in hopes of identifying ways to re-awaken the immune system and force an anti-tumor response. To date, however, few consistent, reproducible, or clinically-relevant effects have been shown using vaccine or autologous cell transfers due in part to the fact that the immunosuppressive mechanisms of the tumor have not been overcome. Much of the research focus has been on re-activating or priming cytotoxic T cells to recognize tumor, in some cases completely disregarding the potential roles that B cells play in immune surveillance or how a solid tumor should be treated to maximize immunogenicity. Here, we will summarize what is currently known about the induction or evasion of humoral immunity via tumor-induced cytokine/chemokine expression and how formation of tertiary lymphoid structures (TLS) within the tumor microenvironment may be used to enhance immunotherapy response.

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“…In a study of a model self-antigen, it was demonstrated that exposure of antigen presenting cells to the cytokine IL-6 led to the processing and presentation of cryptic determinants of an antigen [ 44 ]. Display of cryptic determinants has been described as a cornerstone for activation of self reactive T cells in autoimmunity [ 45 ] and also been documented to occur in anti-tumor immunity [ 46 ]. Cryptic epitopes of self-antigens highly expressed by tumors have been demonstrated to be pivotal targets of therapy that result from qualitative and quantitative differences in antigen handling by APC [ 46 ].…”

Section: Immunological Rationale For Vaccination Strategies Targetingmentioning

confidence: 99%

“…Display of cryptic determinants has been described as a cornerstone for activation of self reactive T cells in autoimmunity [ 45 ] and also been documented to occur in anti-tumor immunity [ 46 ]. Cryptic epitopes of self-antigens highly expressed by tumors have been demonstrated to be pivotal targets of therapy that result from qualitative and quantitative differences in antigen handling by APC [ 46 ]. IL-6 itself has a prominent role in tumor angiogenesis, upregulating VEGF expression [ 47 ].…”

Section: Immunological Rationale For Vaccination Strategies Targetingmentioning

confidence: 99%

Safety of targeting tumor endothelial cell antigens

et al. 2016

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The mechanisms underlying discrimination between “self” and “non-self”, a central immunological principle, require careful consideration in immune oncology therapeutics where eliciting anti-cancer immunity must be weighed against the risk of autoimmunity due to the self origin of tumors. Whole cell vaccines are one promising immunotherapeutic avenue whereby a myriad of tumor antigens are introduced in an immunogenic context with the aim of eliciting tumor rejection. Despite the possibility collateral damage to healthy tissues, cancer immunotherapy can be designed such that off target autoimmunity remains limited in scope and severity or completely non-existent. Here we provide an immunological basis for reconciling the safety of cancer vaccines, focusing on tumor endothelial cell vaccines, by discussing the following topics: (a) Antigenic differences between neoplastic and healthy tissues that can be leveraged in cancer vaccine design; (b) The layers of tolerance that control T cell responses directed against antigens expressed in healthy tissues and tumors; and, (c) The hierarchy of antigenic epitope selection and display in response to whole cell vaccines, and how antigen processing and presentation can afford a degree of selectivity against tumors. We conclude with an example of early clinical data utilizing ValloVax™, an immunogenic placental endothelial cell vaccine that is being advanced to target the tumor endothelium of diverse cancers, and we report on the safety and efficacy of ValloVax™ for inducing immunity against tumor endothelial antigens.

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Cryptic Epitopes Induce High-Titer Humoral Immune Response in Patients with Cancer

Abstract: Material

Cited by 11 publications

References 47 publications

Involvement of Membrane Blebbing in Immunological Disorders and Cancer

Involvement of Membrane Blebbing in Immunological Disorders and Cancer

Role of Tertiary Lymphoid Structures (TLS) in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

Safety of targeting tumor endothelial cell antigens

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