Abstract
BackgroundProgrammed death 1 (PD-1) blockade has great effect in the prevention of oral precancerous lesions, but the drug resistance has also been observed. The determinants of immune resistance during the malignant transformation are poorly understood.MethodsAnti-PD-1 antibody was administered in the 4NQO-induced carcinogenesis mouse models. The mice were then subdivided into PD-1 resistance(PD-1R) group and PD-1 sensitive(PD-1S) group according to the efficacy. The expression of PD-1 and PD-L1, and the abundance of CD3+ T cells in tumor microenvironment between the two groups was tested by immunohistochemistry. In addition, the activation and effector functions, as well as the accumulation of immunosuppressive cells and expression of immune checkpoints of T cells in the draining lymph nodes and spleen between PD-1R and PD-1S group were analyzed by flow cytometry.ResultsOur results showed that T cell infiltration in tumor microenvironment, effector T cell cytokine secretion and central memory T cell accumulation in peripheral lymphoid organs were all inhibited in the anti-PD-1 resistance group. Furthermore, we found that an increase of regulatory T cell (Treg) population contributed to the resistance of the anti-PD-1 therapy. Notably, TIM-3 was found to be the only immunosuppressive molecule that mediated the resistance to anti-PD-1 therapy in the oral malignant transformation model.ConclusionsOur findings identified a novel mechanism that T cell dysfunction contributes to the immune resistance during the malignant transformation of the oral mucosa. This study provides new targets for improving the efficacy of immunotherapy for early stage of tumorigenesis.
Highlights
Programmed death 1 (PD-1) blockade has great effect in the prevention of oral precancerous lesions, but the drug resistance has been observed
Resistance to PD-1 treatment altered the tumor immune microenvironment of the oral precancerous lesions to determine whether the immune microenvironment was altered in the PD-1R group, immunohistochemical staining of PD-1, programmed death ligand 1 (PD-L1) and CD3 were performed on tissue samples from the PD-1R, PD-1S and control IgG groups
The expression of PD-1 and PD-L1 in the PD-1S and PD-1R groups were both lower than that in the control group, and the expression of PD-L1 in PD-1S group is significantly lower than PD-1R group(P < 0.05). c CD3+ T cell infiltration increased in the PD-1S group but decreased in the PD-1R group compared with the control group(P < 0.05)
Summary
Programmed death 1 (PD-1) blockade has great effect in the prevention of oral precancerous lesions, but the drug resistance has been observed. The determinants of immune resistance during the malignant transformation are poorly understood. The response rate was reported to be lower than 35% in advanced malignant melanoma patients administered anti-PD-1 antibodies [7], and in non-small cell lung carcinoma patients, the positive response rate was only 20% [8]. To date, little is known about the mechanism of drug resistance to anti-PD-1 therapy in the context of malignant transformation in oral premalignant lesions. We found T cell dysfunction contributes to the immune resistance during the malignant transformation of the oral mucosa. This study provides new targets for improving the efficacy of immunotherapy for early stage of tumorigenesis
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