Peptide vaccines in breast cancer: The immunological basis for clinical response.

High-grade serous carcinoma (HGSC) is the most lethal ovarian cancer histotype. The fallopian tube secretory epithelial cells (FTSECs) are a proposed progenitor cell type. Genetically altered FTSECs form tumors in mice; however, a spontaneous HGSC model has not been described. Apart from a subpopulation of genetically predisposed women, most women develop ovarian cancer spontaneously, which is associated with aging and lifetime ovulations. A murine oviductal cell line (MOE(LOW)) was developed and continuously passaged in culture to mimic cellular aging (MOE(HIGH)). The MOE(HIGH) cellular model exhibited a loss of acetylated tubulin consistent with an outgrowth of secretory epithelial cells in culture. MOE(HIGH) cells proliferated significantly faster than MOE(LOW), and the MOE(HIGH) cells produced more 2D foci and 3D soft agar colonies as compared to MOE(LOW) MOE(HIGH) were xenografted into athymic female nude mice both in the subcutaneous and the intraperitoneal compartments. Only the subcutaneous grafts formed tumors that were negative for cytokeratin, but positive for oviductal markers, such as oviductal glycoprotein 1 and Pax8. These tumors were considered to be poorly differentiated carcinoma. The differential molecular profiles between MOE(HIGH) and MOE(LOW) were determined using RNA-Seq and confirmed by protein expression to uncover pathways important in transformation, like the p53 pathway, the FOXM1 pathway, WNT signaling, and splicing. MOE(HIGH) had enhanced protein expression of c-myc, Cyclin E, p53, and FOXM1 with reduced expression of p21. MOE(HIGH) were also less sensitive to cisplatin and DMBA, which induce lesions typically repaired by base-excision repair. A model of spontaneous tumorogenesis was generated starting with normal oviductal cells. Their transition to cancer involved alterations in pathways associated with high-grade serous cancer in humans.

/pdf/spontaneous-transformation-of-murine-oviductal-epithelial-47c5i8svvc.pdf

Spontaneous Transformation of Murine Oviductal Epithelial Cells: A Model System to Investigate the Onset of Fallopian-Derived Tumors.

Cancer is the leading cause of death worldwide. In developed as well as developing countries, breast cancer is the most common cancer found among women. Currently, treatment of breast cancer consists mainly of surgery, chemotherapy, hormone therapy, and radiotherapy. In recent years, because of increased understanding of the therapeutic potential of immunotherapy in cancer prevention, cancer vaccines have gained importance. Here, we review various immunotherapeutic breast cancer vaccines including peptide-based vaccines, whole tumor cell vaccines, gene-based vaccines, and dendritic cell vaccines. We also discuss novel nanotechnology-based approaches to improving breast cancer vaccine efficiency.

/pdf/current-approaches-in-development-of-immunotherapeutic-5eopsp3b9h.pdf

Current Approaches in Development of Immunotherapeutic Vaccines for Breast Cancer

Simple Summary Tumor-associated antigens (TAAs) are antigens present in tumor cells, but are also expressed in normal cells. However, TAAs are aberrantly expressed by tumor cells, and can elicit multiple specific immune responses. One key feature of TAAs is the presence of post-translational modifications often absent in normal proteins. This article offers an overview of the role of post-translational modifications in TAAs in eliciting a specific immune response, which makes them targets for immuno-oncology therapy. Both preclinical and clinical studies will be discussed. Abstract Post-translational modifications (PTMs) are generated by adding small chemical groups to amino acid residues after the translation of proteins. Many PTMs have been reported to correlate with tumor progression, growth, and survival by modifying the normal functions of the protein in tumor cells. PTMs can also elicit humoral and cellular immune responses, making them attractive targets for cancer immunotherapy. This review will discuss how the acetylation, citrullination, and phosphorylation of proteins expressed by tumor cells render the corresponding tumor-associated antigen more antigenic and affect the immune response in multiple cancers. In addition, the role of glycosylated protein mucins in anti-cancer immunotherapy will be considered. Mucin peptides in combination with stimulating adjuvants have, in fact, been utilized to produce anti-tumor antibodies and vaccines. Finally, we will also outline the results of the clinical trial exploiting glycosylated-MUC1 as a vaccine in different cancers. Overall, PTMs in TAAs could be considered in future therapies to result in lasting anti-tumor responses.

/pdf/post-translational-modifications-in-tumor-associated-2t6az1eh.pdf

Post-Translational Modifications in Tumor-Associated Antigens as a Platform for Novel Immuno-Oncology Therapies

Induced pluripotent stem cell (iPSC) technology enables the creation and selection of pluripotent cells with specific genetic traits. This report describes a pluripotent cell line created specifically to form replacement pancreatic cells as a therapy for insulin-dependent diabetes. Beginning with primary pancreatic tissue acquired through organ donation, cells were isolated, re-programmed using non-integrating vectors and exposed to a four day differentiation protocol to generate definitive endoderm, a developmental precursor to pancreas. The best performing iPSC lines were then subjected to a 12-day basic differentiation protocol to generate endocrine pancreas precursors. The line that most consistently generated highly pure populations was selected for further development. This approach created an iPSC-variant cell line, SR1423, with a genetic profile correlated with preferential differentiation toward endodermal lineage at the loss of mesodermal potential. This report further describes an improved differentiation protocol that, coupled with SR1423, generated populations of greater than 60% insulin-expressing cells that secrete insulin in response to glucose and are capable of reversing diabetes in rodents. Created and banked following cGMP guidelines, SR1423 is a candidate cell line for the production of insulin-producing cells useful for the treatment of diabetes.

/pdf/generation-and-selection-of-pluripotent-stem-cells-for-oysitwxfv2.pdf

Generation and selection of pluripotent stem cells for robust differentiation to insulin-secreting cells capable of reversing diabetes in rodents.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/ajt.12056

Allograft outcomes in outbred mice

Vaccines are beginning to be explored for as measures to prevent cancer. Since determining the efficacy of vaccines by evaluating disease outcome requires a long time, there is an urgent need for early predictive biomarkers. To this end, immunological endpoints that can be assessed weeks or months post-vaccination are currently being evaluated. However, when multiple vaccines are available, waiting for the development of humoral and cellular immunity could still cause delays, whereas early assessments would allow for a timely shift to more effective prevention modalities. Applying the phospho-flow technique to primary T cells, we examined the phosphorylation status of various proteins that shape the activation, proliferation, and differentiation of mucin 1 (MUC1)-specific CD4+ T cells within the first 24 hours post-immunization. It is known that a vaccine composed of a MUC1-derived peptide loaded on dendritic cells is more effective in eliciting T-cell responses than a vaccine including the same peptide p...

Early in vivo signaling profiles in MUC1-specific CD4+ T cells responding to two different MUC1-targeting vaccines in two different microenvironments

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Allograft outcomes in outbred mice

Early in vivo signaling profiles in MUC1-specific CD4+ T cells responding to two different MUC1-targeting vaccines in two different microenvironments