p62-DNA-encoding plasmid reverts tumor grade, changes tumor stroma, and enhances anticancer immunity

Abstract

Previously, we reported that the administration of a p62/SQSTM1-encoding plasmid demonstrates high safety and clinical benefits for human cancer patients, having also suppressed tumor growth and metastasis in dogs and mouse models. Here we investigated the mechanistic aspects of these effects. In mammary tumors bearing-dogs, p62 plasmid i.m. injections reduced tumor volumes, and reverted tumor grade to less aggressive lesions in 5 out of 6 animals, with one carcinoma switching to benign adenoma. The treatment increased levels of alpha-SMA in stroma cells and collagen 3 in the extracellular matrix, both of which correlate with a good clinical prognosis. p62 treatment also increased the abundance of intratumoral T-cell. To test the role of adaptive immunity, we compared protective effects of the plasmid against B16 melanoma in wild type C57BL/6J mice and in the corresponding SCID strain lacking lymphocytes. The plasmid was only protective in the wild type strain. Also, p62 plasmid amplified anti-tumor effect of adoptive T-cell transfer from tumor-bearing animals to animals challenged with the same tumors. We conclude that the plasmid acts indirectly via re-modeling of the tumor microenvironment, making it more favorable for increased anti-cancer immunity. Thus, the p62-encoding plasmid might be a new adjuvant for cancer treatments.

p62: Friend or Foe? Evidences for OncoJanus and NeuroJanus Roles

“…In accordance, Yan et al have shown that overexpressed wild-type p62 in ovarian cancer cells significantly increased activation of caspase 8, with consequent apoptosis, and ameliorates the response to cisplatin [ 20 ]. Moreover, evidence has been provided that p62 ectopic expression in vivo reverts tumor grade, changes tumor stroma and enhances anticancer immunity [ 87 ]. Even more recently, Choi et al showed increased levels of nuclear p62 upon ascorbic acid treatment in breast cancer cells correlated with endoplasmic reticulum stress and cell death [ 88 ].…”

p62/SQSTM1 indirectly mediates remote multipotent mesenchymal cells and rescues bone loss and bone marrow integrity in ovariectomized rats

“…Recently, the p62 plasmid was reported to act as a promising anticancer agent in rodent laboratory models (F. Venanzi et al, 2013), spontaneous cancers in dogs and cats (Gabai et al, 2014 and unpublished data), and in humans (Ponomarenko et al, 2017, 2020). The plasmid remodels a tumor microenvironment making it more favorable for anticancer treatments (F. M. Venanzi et al, 2019). The p62 plasmid can also partially restore both metabolic and behavioral components of high‐calorie, diet‐induced obesity (Halenova et al, 2017), partially prevent age‐related macular degeneration (Kolosova et al, 2018), and cause bone and bone marrow “rejuvenation” (Agas & Sabbieti, 2021; Agas et al, 2020; Lacava et al, 2019; Sabbieti et al, 2015).…”

“…The plasmid remodels a tumor microenvironment making it more favorable for anticancer treatments (F. M. Venanzi et al, 2019). The p62 plasmid can also partially restore both metabolic and behavioral components of high-calorie, diet-induced obesity (Halenova et al, 2017), partially prevent age-related macular degeneration (Kolosova et al, 2018), and cause bone and bone marrow "rejuvenation" (Agas & Sabbieti, 2021;Agas et al, 2020;Lacava et al, 2019;Sabbieti et al, 2015).…”