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Research Letter | Association of VA Surgeons

Pancreatic Cancer Cell Lysis by Cell-Penetrating Peptide-MAGE-A3–Induced Cytotoxic T Lymphocytes ONLINE FIRST

Ramesh B. Batchu, PhD1,2; Oksana V. Gruzdyn, BS1,2; Aamer M. Qazi, PhD1,2; Ebrahem M. Mahmud, BS1; Gamal Mostafa, MD1,2; Donald W. Weaver, MD1; Scott A. Gruber, MD, PhD, MBA1,2
[+] Author Affiliations
1Wayne State University School of Medicine, Detroit, Michigan
2John D. Dingell VA Medical Center, Detroit, Michigan
JAMA Surg. Published online August 17, 2016. doi:10.1001/jamasurg.2016.2346
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This cell biology study compares cytotoxic T cell lysis of in vitro pancreatic cancer cells with vs without tumor antigen expression induced by cell-penetrating peptide.

In contrast to the therapeutic advances for other malignant neoplasms, the therapeutic advances for pancreatic cancer have been slow, with the 5-year survival rate currently at less than 8% for patients with pancreatic cancer.1 Immunotherapy is a particularly appealing approach to pancreatic cancer owing to its potential for eliminating tumor cells that are often unreachable by conventional therapies and its negligible side effects. Along these lines, dendritic cells (DCs) are central to the generation of effector cytotoxic CD8+ T lymphocytes (CTLs) that recognize tumor-specific antigens (TSAs) expressed on the surface of cancer cells. MAGE-A3 (melanoma antigen family A, 3) is a TSA expressed in a significant fraction of pancreatic cancers,2 thus providing an opportunity for introducing DC-based immunotherapy. However, clinically meaningful antitumor immune responses in DC vaccine trials have been sparse owing, in part, to suboptimal intracellular bioavailability of TSA to HLA class I molecules. Various cell-penetrating peptide (CPP) domains are known to ferry covalently linked heterologous TSAs across the plasma membrane into the cytosolic compartment to access HLA class I molecules.3 We and others have previously demonstrated that CPP effectively increased the intracellular entry of TSAs.4,5 We extend this work by investigating whether DCs pulsed with MAGE-A3 linked to CPP could elicit more effective antitumor CTL responses.

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Figure 1.
Allostimulatory Activities of Dendritic Cells (DCs) and Secreted Cytokine Profile of MAGE-A3–Specific CD8+ T Lymphocytes

A, MAGE-A3 with or without cell-penetrating peptide (CPP)–transduced DCs elicits equipotent allogeneic T lymphocyte proliferation compared with mock-transduced DCs in mixed lymphocyte reaction assay. B, Cytokine secretion profile of MAGE-A3–specific CD8+ T lymphocytes. Data are representative of 3 separate experiments. Error bars indicate SD.

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Figure 2.
Cytotoxicity Assays

Lysis of PANC-1 cell lines by CD8+ T lymphocytes generated by dendritic cells plus MAGE-A3 and by dendritic cells plus cell-penetrating peptide (CPP)–MAGE-A3 (6 experiments). Error bars indicate SD.

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