Whether vaccines are designed to prepare the immune system for the encounter with a pathogen or with cancer, certain common challenges need to be faced, such as what antigen and what adjuvant to use, what type of immune response to generate and how to make it long lasting. Cancer, additionally, presents several unique hurdles. Cancer vaccines must overcome immune suppression exerted by the tumour, by previous therapy or by the effects of advanced age of the patient. If used for cancer prevention, vaccines must elicit effective long-term memory without the potential of causing autoimmunity. This article addresses the common and the unique challenges to cancer vaccines and the progress that has been made in meeting them. Considering how refractory cancer has been to standard therapy, efforts to achieve immune control of this disease are well justified.

/pdf/cancer-vaccines-between-the-idea-and-the-reality-1m8bofvfu1.pdf

Cancer vaccines: between the idea and the reality.

MUC1 is a large, heavily glycosylated mucin expressed on the apical surfaces of most simple, secretory epithelia including the mammary gland, gastrointestinal, respiratory, urinary and reproductive tracts. Although MUC1 was thought to be an epithelial-specific protein, it is now known to be expressed on a variety of hematopoietic cells as well. Mucins function in protection and lubrication of epithelial surfaces. Transmembrane mucins, which contain cytoplasmic tail domains, appear to have additional functions through their abilities to interact with many proteins involved in signal transduction and cell adhesion. The goal of this review is to highlight recent discoveries that suggest that MUC1 may be a multifunctional protein, located on the surfaces of cells as a sensor of the environment, poised to signal to the interior when things go awry.

MUC1, the renaissance molecule.

MUC1 immunobiology: from discovery to clinical applications.

The human epithelial mucin, MUC1, is a large transmembrane glycoprotein that is expressed on most simple epithelia. It is overexpressed and aberrantly glycosylated on many human epithelial tumors, including more than 90% of human breast cancers. MUC1 is of interest as an immunotherapy target because patients with breast, ovarian, and pancreatic cancers have T lymphocytes in their tumor-draining lymph nodes that can be induced to recognize and lyse MUC1-expressing tumor cells. We have produced a transgenic mouse model that expresses the human MUC1 molecule on an inbred C57Bl/6 background to investigate the effect of endogenous expression of MUC1 on the ability of mice to generate antitumor immunity to MUC1-expressing tumors. Transgenic mice expressed the human transgene in a pattern and level consistent with that observed in humans. Transgenic mice were tolerant to stimulation by MUC1 as evidenced by the ability of MUC1-expressing tumor cells to grow in these mice, whereas MUC1-expressing cells were eliminated from wild-type mice. Moreover, transgenic mice immunized with MUC1 peptides failed to exhibit immunoglobulin class switching to the IgG subtypes. These data suggest that endogenous expression of MUC1 protein by MUC1 transgenic mice induces T-cell tolerance to stimulation by MUC1. The transgenic mice will provide a useful model to investigate the mechanisms that regulate immunological tolerance to tumor antigens and will facilitate the investigation of anti-MUC1 immunotherapy formulations.

Tolerance and immunity to MUC1 in a human MUC1 transgenic murine model

Dendritic cells (DCs) are potent antigen-presenting cells and play a pivotal role in T cell-mediated immunity. DCs have been shown to induce strong antitumor immune responses in vitro and in vivo, and their efficacy is being investigated in clinical trials. Compared with vaccination strategies directed against a single tumor antigen, tumor-cell lysate as the source of antigen offers the potential advantage of inducing a broad T-cell response against multiple known, as well as unknown, tumor-associated antigens expressed by the individual tumor. We used pancreatic carcinoma cell lines to develop an in vitro model for monitoring T-cell responses induced by lysate-pulsed DCs. Monocyte-derived DCs of HLA-A2(+) donors were pulsed with lysate generated from the HLA-A2(+) pancreatic carcinoma cell line Panc-1. In some experiments, the immunogenic protein keyhole limpet hemocyanin (KLH) was added to the lysate. Subsequently, the antigen-loaded DCs were activated with tumor necrosis factor-alpha and prostaglandin E(2). Autologous mononuclear cells were cocultured with DCs in the presence of low-dose interleukin (IL)-2 and IL-7 and were restimulated weekly with new DCs. High levels of IL-12 and IFN-gamma could be detected in the supernatants, indicating a T-helper type 1-type immune response. This cytokine profile was associated with the expression of the activation marker CD69 on both T helper and CTLs and with an antigen-induced proliferative T-cell response. After 4 weeks, CTL-mediated cytotoxicity was assessed. Tumor cell lysis was specific for Panc-1 tumor cells and was MHC class I-restricted. Cytokine secretion, CD69 expression of T cells, and antigen-induced T-cell proliferation correlated with the cytotoxic activity and were more pronounced when KLH was added to the lysate. This is the first study to show that T cells specific for pancreatic carcinoma cells can be generated in vitro by lysate-pulsed DCs and that the T-cell response can be enhanced by KLH. This in vitro model can be applied to compare different strategies in the development of DC-based tumor vaccines.

https://cancerres.aacrjournals.org/content/canres/61/17/6445.full.pdf

Tumor cell lysate-pulsed human dendritic cells induce a T-cell response against pancreatic carcinoma cells: an in vitro model for the assessment of tumor vaccines.

Pancreatic cancer is a highly aggressive, treatment refractory cancer and is the fourth leading cause of death in the United States. In humans, 90% of pancreatic adenocarcinomas overexpress altered forms of a tumor-specific Ag, mucin 1 (MUC1; an epithelial mucin glycoprotein), which is a potential target for immunotherapy. We have established a clinically relevant animal model for pancreatic cancer by developing a double transgenic mouse model (called MET) that expresses human MUC1 as self molecule and develops spontaneous tumors of the pancreas. These mice exhibit acinar cell dysplasia at birth, which progresses to microadenomas and acinar cell carcinomas. The tumors express large amounts of underglycosylated MUC1 similar to humans. Tumor-bearing MET mice develop low affinity MUC1-specific CTLs that have no effect on the spontaneously occurring pancreatic tumors in vivo. However, adoptive transfer of these CTLs was able to completely eradicate MUC1-expressing injectable tumors in MUC1 transgenic mice, and these mice developed long-term immunity. These CTLs were MHC class I restricted and recognized peptide epitopes in the immunodominant tandem repeat region of MUC1. The MET mice appropriately mimic the human condition and are an excellent model with which to elucidate the native immune responses that develop during tumor progression and to develop effective antitumor vaccine strategies.

/pdf/mice-with-spontaneous-pancreatic-cancer-naturally-develop-40m30rzg3c.pdf

Mary J. Tevethia

Papers

Mice with Spontaneous Pancreatic Cancer Naturally Develop MUC-1-Specific CTLs That Eradicate Tumors When Adoptively Transferred