6P - CD161+CD127+CD8+ T cells as a critical predictor of the efficacy of anti-PD-1 immunotherapy in diabetic patients with non-small cell lung cancer

Background

PD-1-based immunotherapy is used for first- or second-line therapeutic regimens against NSCLC. Anti-PD-1 immunotherapy resistance occurs in diabetic patients with NSCLC. However, the characteristics of immune cell infiltration in such patients remain unexplored. Thus, we investigated the possible link between diabetes and immune cell infiltration in NSCLC.

Methods

We included patients (n = 437) with NSCLC treated with anti-PD-1 immunotherapy from the Zhejiang University School of Medicine. We analyzed the objective response rate, progression-free survival (PFS), overall survival (OS), T-cell infiltration, and peripheral blood immunological characteristics in diabetic and nondiabetic NSCLC patients. Differences in tumor microenvironment profiles were measured using CyTOF to elucidate the reasons for poor PFS and OS in diabetic NSCLC patients.

Results

Nondiabetic NSCLC patients had longer PFS than diabetic NSCLC patients (11.0 vs 7.0 months). The OS was 24.0 and 17.0 months in nondiabetic and diabetic NSCLC patients, respectively (P = 0.0065). Diabetic NSCLC patients had significantly lower CD8+T cell infiltration than nondiabetic NSCLC patients (P = 0.0227). Similarly, the anti-tumor effect of PD-1 blockade was decreased in diabetic mice with lung cancer. Additionally, compared with nondiabetic NSCLC patients before anti-PD1 treatment, CyTOF analysis showed that diabetic NSCLC patients had significantly more CD161⁺CD127⁺CD8⁺ T cells (P = 0.0071), and this trend continued after anti-PD1 treatment (P = 0.0393). Flow cytometry showed that diabetic NSCLC patients had a significantly higher CD161⁺CD127⁺CD8⁺T/CD8⁺ T cells ratio than nondiabetic NSCLC patients. Kaplan–Meier survival analysis showed that high levels of CD161⁺CD127⁺CD8⁺ T cells were positively related to the PFS in diabetic NSCLC patients.

Conclusions

We confirmed that diabetes is a risk factor for patients with NSCLC who undergo anti-PD-1 immunotherapy. CD161⁺CD127⁺CD8⁺ T cells in diabetic NSCLC patients serve as a key indicator of poor prognosis. Our findings provide a reference for understanding the characteristics of the tumor microenvironment in diabetic NSCLC patients.

Editorial acknowledgement

Prof. Nong Yang from the Lung Cancer and Gastroenterology Department, Hunan Cancer Hospital, and the Affiliated Tumor Hospital of Xiangya Medical School of Central South University for their technical support. Editage for English language editing.

Legal entity responsible for the study

Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, P. R. China.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81802278), Natural Science Foundation of Zhejiang Province (No.LY23H160020), Medicine Health Technology Plan of Zhejiang Province, China (No. 2022KY150), and General Project of Education Department of Zhejiang Province (Y202043420).

Disclosure

All authors have declared no conflicts of interest.