Local Anti–PD-1 Delivery Prevents Progression of Premalignant Lesions in a 4NQO-Oral Carcinogenesis Mouse Model

Abstract

While the principle of systemic treatment to prevent the progression of oral premalignant lesions (OPLs) has been demonstrated, there remains a lack of consensus about an optimal approach which balances clinical efficacy with toxicity concerns. Recent advances in cancer therapy using approaches targeting the tumor immune microenvironment (TIME) including immune checkpoint inhibitors indicate that these agents have significant clinically activity against different types of cancer including oral cancer and therefore they may provide and effective oral cancer prevention strategy for patients with OPLs. Our past work showed that systemic delivery of a monoclonal antibody to the PD-1 immune checkpoint can inhibit the progression of OPLs to oral cancer in a syngeneic murine oral carcinogenesis model. Here we report a novel approach of local delivery of a PD1 immune checkpoint inhibitor loaded using a hydrogel, which significantly reduces the progression of OPLs to carcinomas. In addition, we detected a significant infiltration of regulatory T cells associated with oral lesions with p53 mutation, and a severe loss of expression of STING which correlated with a decreased infiltration of dendritic cells in the oral lesions. However, a single local dose of PD1 inhibitor was found to restore STING and CD11c expression and increase the infiltration of CD8 T cells into the TIME irrespective of the p53 mutational status.Overall, we provide evidence for the potential clinical value of local delivery of biomaterials loaded with anti-PD-1 antibodies to prevent malignant progression of OPLs.

Genetic Changes Driving Immunosuppressive Microenvironments in Oral Premalignancy

“…Furthermore, we detected that the protein levels of STING were significantly lower in OPLs expressing mutant Trp53-R172H compared with wild-type Trp53. In addition, we observed a significant reduction of infiltrated DC cells in OPLs expressing mutant p53 (88). While infiltrating immune cells retain wild-type p53 and have normal STING, mutant p53 OPLs have decreased immune cell infiltration and may not compensate for reduced STING expression in lesions with mutant TP53.…”

“…This study not only showed the capacity of the hydrogels to control the release of PD-1 antibody and reduce OPL frequency, but also provided evidence of the role of mutant p53 in the mechanism of immunosuppression in OPLs. Other immunoprevention studies using p53 mutant mice have showed similar results but required 8 doses of parental immunotherapy administration (89,123), compared to a single hydrogel-PD1 dose (88). A recent comprehensive study of patient samples of leukoplakia identified that proliferative leukoplakia predicts a high rate of malignant transformation within 5 years of diagnosis.…”

“…Next, hydrogels were implanted in three histological regions of the tongue to increase the ICI biodistribution. Interestingly, OPLs frequency was significantly reduced in p53 wild type mice, however high-risk OPLs were higher in mutant p53 mice ( 88 ). This study not only showed the capacity of the hydrogels to control the release of PD-1 antibody and reduce OPL frequency, but also provided evidence of the role of mutant p53 in the mechanism of immunosuppression in OPLs.…”

“…This carcinogenesis model exhibits similar histological, molecular and chromosomal alterations as observed in human oral carcinogenesis ( 86 , 87 ). We and others have recently reported that 4NQO induced oral lesions expressing mutant Trp53 -R172H contain a higher infiltration of FoxP3+ T regulatory cells (Tregs) compared to Trp53 wild-type mice ( 88 , 89 ). It is known that Tregs are suppressors of antitumor responses that disrupt the maturation of dendritic cells (DC) and prevent the activation of CD4 + effector and CD8 + cytotoxic cells in the tumor microenvironment ( 90 ).…”

“…Targeting immunosuppressive molecules may serve as an effective strategy to treat oral dysplasia and prevent malignant progression. Treatment with PD-1 blockade decreased the incidence of dysplastic lesions and invasive OSCC in a carcinogen induced 4-NOQ OPLs model ( 88 ). The Heymach group further compared several different checkpoint inhibitors including CD40, PD-1, CTLA04 and OX40, on OPL progression during oral carcinogenesis.…”