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

Area of Science:

• Oncology
• Immunology
• Gene Therapy

Background:

• Previous studies reported safety and clinical benefits of p62/SQSTM1-encoding plasmid in cancer patients.
• The plasmid suppressed tumor growth and metastasis in canine and murine models.

Purpose of the Study:

• To investigate the mechanistic aspects of p62/SQSTM1 plasmid's anti-cancer effects.
• To elucidate the role of the tumor microenvironment and adaptive immunity in the plasmid's efficacy.

Main Methods:

• Administration of p62 plasmid via intramuscular injections in mammary tumor-bearing dogs.
• Comparison of p62 plasmid efficacy in wild-type versus severe combined immunodeficient (SCID) mice against B16 melanoma.
• Assessment of tumor size, aggressive potential, stromal cell markers, extracellular matrix components, and intratumoral T-cell abundance.

Main Results:

• p62 plasmid treatment reduced tumor size and aggressiveness in 5 out of 6 dogs, with one carcinoma regressing to adenoma.
• Increased levels of smooth muscle actin and type III collagen in the tumor stroma, correlating with good prognosis.
• Enhanced intratumoral T-cell abundance and protective effects were observed only in immunocompetent wild-type mice, not in SCID mice.
• p62 plasmid amplified the anti-tumor effects of T-cell transfer.

Conclusions:

• The p62/SQSTM1-encoding plasmid effectively remodels the tumor microenvironment.
• The plasmid enhances anti-cancer immunity, particularly adaptive T-cell responses.
• p62 plasmid represents a potential novel adjuvant therapy for cancer treatment.