Abstract
Autophagy plays an important role in neoplastic transformation of cells and in resistance of cancer cells to radio- and chemotherapy. p62 (SQSTM1) is a key component of autophagic machinery which is also involved in signal transduction. Although recent empirical observations demonstrated that p62 is overexpressed in variety of human tumors, a mechanism of p62 overexpression is not known. Here we report that the transformation of normal human mammary epithelial cells with diverse oncogenes (RAS, PIK3CA and Her2) causes marked accumulation of p62. Based on this result, we hypothesized that p62 may be a feasible candidate to be an anti-cancer DNA vaccine. Here we performed a preclinical study of a novel DNA vaccine encoding p62. Intramuscularly administered p62-encoding plasmid induced anti-p62 antibodies and exhibited strong antitumor activity in four models of allogeneic mouse tumors - B16 melanoma, Lewis lung carcinoma (LLC), S37 sarcoma, and Ca755 breast carcinoma. In mice challenged with Ca755 cells, p62 treatment had dual effect: inhibited tumor growth in some mice and prolonged life in those mice which developed tumor size similar to control. P62-encoding plasmid has demonstrated its potency both as a preventive and therapeutic vaccine. Importantly, p62 vaccination drastically suppressed metastasis formation: in B16 melanoma where tumor cells where injected intravenously, and in LLC and S37 sarcoma with spontaneous metastasis. Overall, we conclude that a p62-encoding vector(s) constitute(s) a novel, effective broad-spectrum antitumor and anti-metastatic vaccine feasible for further development and clinical trials.
Highlights
Immunotherapy is a rapidly developing approach toward cancer therapy
Multiple approaches have been tested providing a basis for hope that this bottleneck can be resolved, including advanced methods of delivery, novel adjuvants and methods of antigen modifications designed for DNA vaccines [8, 9], heterologous prime-boost vaccination regimens [1012], combination with immunomodulators like anti-PD1 or anti-CTLA-4 antibody, or antagonists of A2A receptor [13]
We describe a novel DNA vaccine based on p62 protein that is critical for cancer and dispensable for normal tissues. p62 performs two major functions in the cell – it is involved in autophagy [15, 16], and serves as a signaling hub for several signal transduction pathways such as NF-kB, p38, TRAF6, protein kinases etc [17]
Summary
Immunotherapy is a rapidly developing approach toward cancer therapy. Several immune modulators such as anti-PD1 or anti-CTLA-4 antibody have been successfully used in clinics and in the FDA approval process [1]. From the perspective of vaccine development, the broad spectrum of human tumors demonstrate highly elevated p62 expression levels as compared to normal tissue [19,20,21]. Based on high intratumoral p62 level, together with the fact that p62 is indispensable for tumor formation and/or progression, we hypothesized that p62 may provide significant benefits as a potent antigen candidate for selective DNA vaccine, which a cancer would not be able to escape.
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