CD161+CD127+CD8+ T cell subsets can predict the efficacy of anti-PD-1 immunotherapy in non-small cell lung cancer with diabetes mellitus

Jingjing Qu; Yuekang Li; Binggen Wu; Qian Shen; Lijun Chen; Wenjia Sun; Bo Wang; Lixiong Ying; Li Wu; Hong Zhou; Jianya Zhou; Jianying Zhou

doi:10.1080/2162402X.2024.2371575

CD161⁺CD127⁺CD8⁺ T cell subsets can predict the efficacy of anti-PD-1 immunotherapy in non-small cell lung cancer with diabetes mellitus

Oncoimmunology. 2024 Jun 27;13(1):2371575. doi: 10.1080/2162402X.2024.2371575. eCollection 2024.

Authors

Jingjing Qu^{1

2}, Yuekang Li^{1

2}, Binggen Wu^{1

2}, Qian Shen^{1

2}, Lijun Chen³, Wenjia Sun^{1

2}, Bo Wang⁴, Lixiong Ying⁴, Li Wu⁵, Hong Zhou¹, Jianya Zhou^{1

2}, Jianying Zhou^{1

2}

Affiliations

¹ Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China.
² The Clinical Research Center for Respiratory Diseases of Zhejiang Province, Hangzhou, Zhejiang, P. R. China.
³ State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China.
⁴ Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China.
⁵ Department of Endocrinology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China.

Abstract

The role of CD161⁺CD127⁺CD8⁺ T cells in non-small cell lung cancer (NSCLC) patients with diabetes remains unexplored. This study determined the prevalence, phenotype, and function of CD8⁺ T cell subsets in NSCLC with diabetes. We recruited NSCLC patients (n = 436) treated with anti-PD-1 immunotherapy as first-line treatment. The progression-free survival (PFS), overall survival (OS), T cells infiltration, and peripheral blood immunological characteristics were analyzed in NSCLC patients with or without diabetes. NSCLC patients with diabetes exhibited shorter PFS and OS (p = 0.0069 and p = 0.012, respectively) and significantly lower CD8⁺ T cells infiltration. Mass cytometry by time-of-flight (CyTOF) showed a higher percentage of CD161⁺CD127⁺CD8⁺ T cells among CD8⁺T cells in NSCLC with diabetes before anti-PD-1 treatment (p = 0.0071) than that in NSCLC without diabetes and this trend continued after anti-PD-1 treatment (p = 0.0393). Flow cytometry and multiple-immunofluorescence confirmed that NSCLC with diabetes had significantly higher CD161⁺CD127⁺CD8⁺ T cells to CD8⁺T cells ratios than NSCLC patients without diabetes. The RNA-sequencing analysis revealed immune-cytotoxic genes were reduced in the CD161⁺CD127⁺CD8⁺ T cell subset compared to CD161⁺CD127^-CD8⁺ T cells in NSCLC with diabetes. CD161⁺CD127⁺CD8⁺ T cells exhibited more T cell-exhausted phenotypes in NSCLC with diabetes. NSCLC patients with diabetes with ≥ 6.3% CD161⁺CD127⁺CD8⁺ T cells to CD8⁺T cells ratios showed worse PFS. These findings indicate that diabetes is a risk factor for NSCLC patients who undergo anti-PD-1 immunotherapy.CD161⁺CD127⁺CD8⁺ T cells could be a key indicator of a poor prognosis in NSCLC with diabetes. Our findings would help in advancing anti-PD-1 therapy in NSCLC patients with diabetes.

Keywords: CD161+CD127+CD8+ T cells; diabetes mellitus; immunotherapy; non-small cell lung cancer; predictive biomarkers.

MeSH terms

Adult
Aged
CD8-Positive T-Lymphocytes* / immunology
Carcinoma, Non-Small-Cell Lung* / drug therapy
Carcinoma, Non-Small-Cell Lung* / immunology
Diabetes Mellitus / drug therapy
Diabetes Mellitus / immunology
Female
Humans
Immune Checkpoint Inhibitors / pharmacology
Immune Checkpoint Inhibitors / therapeutic use
Immunotherapy / methods
Interleukin-7 Receptor alpha Subunit / metabolism
Lung Neoplasms* / drug therapy
Lung Neoplasms* / immunology
Male
Middle Aged
Prognosis
Programmed Cell Death 1 Receptor / antagonists & inhibitors
T-Lymphocyte Subsets / drug effects
T-Lymphocyte Subsets / immunology
T-Lymphocyte Subsets / metabolism

Substances

Programmed Cell Death 1 Receptor
Immune Checkpoint Inhibitors
Interleukin-7 Receptor alpha Subunit

Grants and funding

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