Early Effector T Lymphocytes Coexpress Multiple Inhibitory Receptors in Primary Non-Small Cell Lung Cancer

Area of Science:

• Immunology
• Oncology
• Cancer Research

Background:

• PD-1/PD-L1 cancer immunotherapy efficacy depends on reactivating tumor-specific T cells.
• Early-stage tumors may harbor T cells not yet functionally impaired by the tumor microenvironment.

Purpose of the Study:

• To identify and characterize T cells in early-stage primary tumors that could be targets for immunotherapy.
• To investigate the phenotype and function of T cells in early-stage non-small cell lung cancer.

Main Methods:

• Flow cytometry analysis of tumor-infiltrating lymphocytes (TILs) from early-stage primary tumors.
• Phenotypic characterization of T cells, including expression of PD-1, inhibitory receptors (TIM-3, CTLA-4, LAG-3, TIGIT), and activation markers (HLA-DR, FOXP3).
• Functional assessment of identified T cell subsets, including cytokine production (IL2, IFNγ) and degranulation (CD107a).

Main Results:

• Activated T cells with an effector memory (T_EM) profile (HLA-DR⁺) were enriched in early-stage lesions.
• TILs coexpressed PD-1 with multiple inhibitory receptors but maintained a recently activated, nonexhausted phenotype.
• A subset of CD8⁺PD-1⁺FOXP3⁺ T cells, termed "early effector cells" (EEC), were identified at the earliest functional differentiation phase.
• EECs exhibited an activated, nonexhausted phenotype, expressed multiple inhibitory receptors, and upon stimulation with autologous tumor, produced IL2 and IFNγ, upregulated CD107a, and were competent for differentiation.

Conclusions:

• The identification of EECs in early-stage tumors provides insights into the early adaptive antitumor immune response.
• These findings support the rationale for investigating immunotherapy, such as PD-1/PD-L1 blockade, in early-stage non-small cell lung cancer.
• EEC characterization offers a potential biomarker for early immune surveillance and therapeutic intervention.