Lung cancer remains the leading cause of cancer deaths worldwide and is the most common cancer in males. Immune-checkpoint inhibitors (ICIs) that target programmed cell death protein-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) have achieved impressive efficacy in the treatment of non-small-cell lung cancer (NSCLC) (Pardoll, 2012; Champiat et al., 2016; Gao et al., 2022). Although ICIs are usually well tolerated, they are often accompanied by immune-related adverse events (irAEs) (Doroshow et al., 2019). Non-specific activation of the immune system produces off-target immune and inflammatory responses that can affect virtually any organ or system (O'Kane et al., 2017; Puzanov et al., 2017). Compared with adverse events caused by chemotherapy, irAEs are often characterized by delayed onset and prolonged duration and can occur in any organ at any stage of treatment, including after cessation of treatment (Puzanov et al., 2017; von Itzstein et al., 2020). They range from rash, pneumonitis, hypothyroidism, enterocolitis, and autoimmune hepatitis to cardiovascular, hematological, renal, neurological, and ophthalmic irAEs (Nishino et al., 2016; Kumar et al., 2017; Song et al., 2020). Hence, we conducted a retrospective study to identify validated factors that could predict the magnitude of the risk of irAEs in patients receiving PD-1/PD-L1 inhibitors; our approach was to analyze the correlation between the clinical characteristics of patients at the start of treatment and relevant indicators such as hematological indices and the risk of developing irAEs. Then, we developed an economical, practical, rapid, and simple model to assess the risk of irAEs in patients receiving ICI treatment, as early as possible.
Male ; Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Lung Neoplasms/drug therapy* ; Immune Checkpoint Inhibitors/adverse effects* ; Programmed Cell Death 1 Receptor ; Retrospective Studies ; Apoptosis

The heterogeneity of exhausted T cells (Tex) is a critical determinant of immune checkpoint blockade therapy efficacy. However, few studies have explored exhausted T cell subpopulations in human cancers. In the present study, we examined samples from two cohorts of 175 patients with head and neck squamous cell cancer (HNSCC) by multiplex immunohistochemistry (mIHC) to investigate two subsets of Tex, CD8⁺PD1⁺TCF1⁺ progenitor exhausted T cells (TCF1⁺Tex^prog) and CD8⁺PD1⁺TCF1^- terminally exhausted T cells (TCF1^-Tex^term). Moreover, fresh tumor samples from 34 patients with HNSCC were examined by flow cytometry and immunohistochemistry to further investigate their properties and cytotoxic capabilities and their correlation with regulatory T cells (Tregs) in the tumor immune microenvironment (TIME). mIHC and flow cytometry analysis showed that TCF1^-Tex^term represented a greater proportion of CD8⁺PD1⁺Tex than TCF1⁺Tex^prog in most patients. TCF1⁺Tex^prog produced abundant TNFα, while TCF1^-Tex^term expressed higher levels of CD103, TIM-3, CTLA-4, and TIGIT. TCF1^-Tex^term exhibited a polyfunctional TNFα⁺GZMB⁺IFNγ⁺ phenotype; and were associated with better overall survival and recurrence-free survival. The results also indicated that larger proportions of TCF1^-Tex^term were accompanied by an increase in the proportion of Tregs. Therefore, it was concluded that TCF1^-Tex^term was the major CD8⁺PD1⁺Tex subset in the HNSCC TIME and that these cells favor patient survival. A high proportion of TCF1^-Tex^term was associated with greater Treg abundance.
CD8-Positive T-Lymphocytes ; Head and Neck Neoplasms/therapy* ; Humans ; Immunotherapy/methods* ; Prognosis ; Programmed Cell Death 1 Receptor ; Squamous Cell Carcinoma of Head and Neck/therapy* ; Tumor Microenvironment ; Tumor Necrosis Factor-alpha