Contributions of T cell dysfunction to the resistance against anti-PD-1 therapy in oral carcinogenesis

Abstract

Background Programmed 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. Methods Anti-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. Results Our 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. Conclusions Our 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. Electronic supplementary material The online version of this article (10.1186/s13046-019-1185-0) contains supplementary material, which is available to authorized users.

Porphyromonas gingivalis Promotes Oral Squamous Cell Carcinoma Progression in an Immune Microenvironment

“…Harvested oral lesions for hematoxylin and eosin (H&E) staining and IHC were stained as previously described (Wen et al 2019). Samples for immunofluorescence (IF) were embedded in OCT compound (Sakura Tissue-Tek) and sectioned into 8-µm sections.…”

CSMD1 Mutations Are Associated with Increased Mutational Burden, Favorable Prognosis, and Anti-Tumor Immunity in Gastric Cancer

“…We speculated that there may be a relationship between mutations of the PHA02927 domain in the CSMD1-mut samples and the enrichment of the above immune signaling pathways, the infiltration of anti-tumor immune cells, and the upregulation of PD-L1, which was related to the relatively good prognosis of patients with gastric cancer. In addition, Treg cells not only play a suppressive role in anti-tumor immunity but also may participate in anti-PD-1/PD-L1 resistance mechanisms [24,25]. Patients with CSMD1-mut had less Treg cells and higher PD-L1 expression, which helped them benefit more from anti-PD-L1 and to less likely develop drug resistance.…”

LncRNA IFITM4P promotes immune escape by up-regulating PD-L1 via dual mechanism in oral carcinogenesis

“…[19][20][21] However, Wen et al found that the PD-1 mAb was less than 70% effective in treating oral precancerous lesions. 22 Levingston and Young found that the PD-1 mAb was temporarily effective in low-grade precancerous lesions and was significantly invalid in high-grade precancerous lesions to carcinoma in situ. 23 These studies basically confirmed that there was immune escape at the stage of OL or precancerous lesions.…”