Contributions of T cell dysfunction to the resistance against anti-PD-1 therapy in oral carcinogenesis
Liling Wen1, Huanzi Lu1, Qiusheng Li1
1Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Stomatological Hospital, Sun Yat-Sen University, No.56, Lingyuan West Road, Yuexiu District, Guangzhou, 510055, Guangdong, People's Republic of China.
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.
Insights
Immune resistance to anti-PD-1 therapy in oral precancerous lesions is linked to T cell dysfunction and increased regulatory T cells (Tregs). TIM-3 was identified as a key mediator of this resistance, offering new therapeutic targets.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Programmed death 1 (PD-1) blockade shows efficacy in preventing oral precancerous lesions.
- Drug resistance to PD-1 blockade is a significant clinical challenge.
- Mechanisms underlying immune resistance in oral malignant transformation remain unclear.
Purpose of the Study:
- To investigate the determinants of immune resistance to anti-PD-1 therapy in oral carcinogenesis.
- To identify novel molecular targets for overcoming resistance to immunotherapy in early-stage oral tumors.
Main Methods:
- Utilized 4NQO-induced oral carcinogenesis mouse models treated with anti-PD-1 antibody.
- Classified mice into PD-1 resistant (PD-1R) and sensitive (PD-1S) groups.
- Analyzed immune cell populations, cytokine secretion, and immune checkpoint expression via immunohistochemistry and flow cytometry.
Main Results:
- PD-1 resistance was associated with inhibited T cell infiltration and effector function.
- An increased regulatory T cell (Treg) population was identified as a contributor to PD-1 resistance.
- TIM-3 was the sole immunosuppressive molecule mediating resistance in this oral malignant transformation model.
Conclusions:
- T cell dysfunction represents a novel mechanism of immune resistance in oral mucosal malignant transformation.
- This study highlights TIM-3 and T cell dysfunction as potential targets to enhance immunotherapy efficacy in early tumorigenesis.
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