Abstract
Previously, we reported that the administration of a p62/SQSTM1-encoding plasmid demonstrates high safety and signs of clinical benefits for human cancer patients. The treatment also suppressed tumor growth and metastasis in dogs and mouse models. Here we investigated some mechanistic aspects of these effects. In mammary tumors bearing-dogs, i.m. injections of p62 plasmid reduced tumor sizes and their aggressive potential in 5 out of 6 animals, with one carcinoma switching to adenoma. The treatment increased levels of smooth muscle actin in stroma cells and type III collagen in the extracellular matrix, which correlate with a good clinical prognosis. The p62 treatment also increased the abundance of intratumoral T-cells. Because of the role of adaptive immunity cannot be tested in dogs, we compared the protective effects of the p62 plasmid against B16 melanoma in wild type C57BL/6J mice versus their SCID counterpart lacking lymphocytes. The plasmid was only protective in the wild type strain. Also, p62 plasmid amplified the anti-tumor effect of T-cell transfer from tumor-bearing animals to animals challenged with the same tumors. We conclude that the plasmid acts 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.
Highlights
Recent advances in cancer immunotherapy, immune checkpoint blockade therapy, have dramatically changed the therapeutic strategy against advanced malignancies [1]
Growing evidences suggest that the major barrier to more successful cancer immuno/chemotherapy is the tumor microenvironment (TME), where chronic inflammation has a predominant role in tumor survival and proliferation, angiogenesis and immunosuppression [2,3,4,5]
The anti-tumor effects of p62 DNA has been evaluated in a cohort of six (6) dogs bearing simple mammary tumors (Table 1)
Summary
Recent advances in cancer immunotherapy, immune checkpoint blockade therapy, have dramatically changed the therapeutic strategy against advanced malignancies [1]. This data raises the question of whether p62 plasmid can alter the TME in a way favorable for anti-cancer immune response Another line of research revealed that administering the p62 plasmid reduces systemic chronic inflammation in rodent models resulting in the prevention and / or alleviation of a number of diseases. Solid and tubulopapillary mammary carcinomas reveal both histological and molecular homology to human breast carcinomas [34] Of note, in both canine mammary tumors and in human prostate cancer, the number of intratumoral T-lymphocytes is reported to be higher in benign lesions than in their malignant counterparts [35, 36]. Testing the effect(s) of a cancer treatment on canine model may provide valuable comparative oncology clues
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