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Active immunization combined with cisplatin confers enhanced therapeutic protection and prevents relapses of HPV-induced tumors at different anatomical sites.

ABSTRACT: The active immunotherapy concept relies on the use of vaccines that are capable of inducing antitumor immunity, reversion of the suppressive immunological environment, and long-term memory responses. Previously, antitumor vaccines based on a recombinant plasmid (pgDE7h) or a purified protein (gDE7) led to regression of early-established human papillomavirus (HPV)-associated tumors in a preclinical model. In this work, the anticancer vaccines were combined with cisplatin to treat HPV-induced tumors at advanced growth stages. The antitumor effects were evaluated in terms of tumor regression, induction of specific CD8⁺ T cells, and immune modulation of the tumor microenvironment. Acute toxicity induced by the treatment was measured by weight loss and histological alterations in the liver and kidneys. Our results revealed that the combination of cisplatin with either one of the tested immunotherapies (pgDE7h or gDE7) led to complete tumor regression in mice. Also, the combined treatment resulted in synergistic effects, particularly among mice immunized with gDE7, including activation of systemic and tumor-infiltrating E7-specific CD8⁺ T cells, tumor infiltration of macrophages and dendritic cells, and prevention of tumor relapses at different anatomical sites. Furthermore, the protocol allowed the reduction of cisplatin dosage and its intrinsic toxic effects, without reducing antitumor outcomes. These results expand our knowledge of active immunotherapy protocols and open perspectives for alternative treatments of HPV-associated tumors.

SUBMITTER: Porchia BFMM

PROVIDER: S-EPMC8692155 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cisplatin is an antineoplastic agent used in the treatment of various types of solid tumors. Despite the dose-dependency of its antineoplastic effect, the high risk for nephrotoxicity frequently precludes the use of higher doses. ?-Linolenic acid (ALA), a carboxylic acid having three cis double bonds, is an essential fatty acid required for health and can be acquired via foods that contain ALA or supplementation of foods high in ALA. Previous studies have shown that ALA demonstrates anti-cancer, anti-inflammatory, and anti-oxidative effects. In this study, we show the protective effect of ALA on cisplatin-induced renal toxicity associated with oxidative stress in mice using biochemical parameters. The mice were randomly assigned into four experimental groups. Group 1 (control group) were administered physiological saline solution for 9 days; group 2 (ALA group) received 200 mg/kg alpha-linolenic acid via gavage for 9 days; group 3 (CIS group) received 100 mg/kg intraperitoneal (i.p.) CIS for 9 days; and group 4 (ALA?+?CIS group) received 100 mg/kg i.p. CIS and followed by ALA 200 mg/kg via gavage for 9 days. Alpha-linolenic acid significantly reduced the expression of myeloperoxidase (MPO), phospholipase A2 (PLA2), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the ALA?+?CIS group compared to the CIS group. Furthermore, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) quantities were significantly elevated in the ALA?+?CIS group when compared to the CIS group. ALA significantly decreased the levels of Bax and cleaved caspase-3, while significantly increasing the level of bcl-2, an anti-apoptotic protein, in the ALA?+?CIS group than in the CIS group. Finally, histopathological examination in renal tissue showed that the significant edematous damage induced by CIS administration alone was reduced in ALA?+?CIS group. In conclusion, our findings show that ALA is beneficial to CIS-induced nephrotoxicity in mice via its anti-inflammatory and anti-oxidative effects.

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Active immunization combined with cisplatin confers enhanced therapeutic protection and prevents relapses of HPV-induced tumors at different anatomical sites.

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