GZMK (Granzyme K)

Upon external validation, the genes GZMK, GZMA, ITGAL, and IL7R were modifiable with ICI and associated with improved overall survival. Further investigation is needed to assess if patients with low baseline expression of these genes may benefit from ICI around the time of surgery.

Hypopharyngeal squamous cell carcinoma (HPSCC), an aggressive head and neck cancer with dismal prognosis, faces persistent chemoresistance to standard TPF (docetaxel, cisplatin, 5-fluorouracil) regimen. Mechanistically, bioinformatics and in vitro coculture data reveal that ZNF683+ NK cells directly interact with CD8+ T cells, and drive an MHC-I-dependent licensing of polyfunctional GZMK+CD8+ effector memory T cells. Collectively, this NK-CD8+ axis provides a potential predictive biomarker and therapeutic target to overcome chemoresistance in patients with HPSCC.

In the absence of perforin, GZMK acquires an immunosuppressive function through F2RL1 activation on tumor cells, which in turn promotes the formation of an immune-suppressive niche. Accordingly, combined targeting of the GZMK/F2RL1 axis and the PD-1/PD-L1 pathway represents a promising synergistic strategy to overcome immune evasion in LUAD.

This discovery suggests a new mechanism for TCR involvement in irAE myocarditis, focusing on T cell activation through the TCR's functional promiscuity, which relies more on TCR-MHC interactions than on specific peptide features. Overall, this research provides a foundation for new strategies targeting TCR physical properties to reduce risks and develop more precise therapies for vulnerable patients.

The major risk factor for ICI myocarditis is the use of combination ICI treatment, especially when relatlimab, a novel anti-LAG-3 (lymphocyte-activation gene 3) antibody, is combined with anti-PD-1 (programmed cell death protein 1) therapy...Treatment with anti-CXCR6 antibody prevented premature lethality, attenuated arrhythmias, and reduced the histological severity of myocarditis, demonstrating that CXCR6+ T cells are necessary for disease pathogenesis. Our findings suggest that ICI myocarditis is driven by an expansion of CXCR6+ T cells and identifies CXCR6 as a putative therapeutic target for this highly morbid condition.

These findings suggest the presence of the Th7R-Tpex axis. Th7R, which reflects antitumor T-cell immunity, is a useful predictive marker for treatment efficacy in ES-SCLC.

This study provides an integrative single-cell and spatial atlas of CRC, revealing structured epithelial-T cell communication and spatial architecture within the tumor microenvironment. Our findings offer novel insights into immune-epithelial crosstalk and identify signaling pathways that may serve as therapeutic targets or biomarkers for CRC precision treatment.

Our data provide a structural basis for inflammaging, where fibroblasts orchestrate the complex immune aging phenotype in non-immune tissues, increasing susceptibility to age-related diseases. Bronchus-associated lymphoid tissue (BALT) enriched for GZMK+ T cells develop with ageLung adventitial fibroblasts demonstrate increased NF-kB activation with age.Fibroblast activation of NF-kB in young animals recapitulates multiple features of normal lung immune agingDepletion of GZMK+ cells decreases lung inflammation in a mouse model of acute respiratory distress syndrome (ARDS).

Subsequent multiplex immunofluorescence imaging of more than 450 primary PDAC tumors showed that the density of antigen-presenting cell (APC):Th:CTL three-cell-type clusters was correlated with intratumoral T-cell clonal expansion and improved overall survival. These findings suggest that DC:Th:CTL triads are conserved across solid tumors and highlight the importance of intratumoral spatial niches in mediating endogenous antitumor immunity.

The TF-miRNA regulatory network analysis uncovered 6 transcription factors (STAT5A/B, NFKB1, EGR1, RELA, and CTCF) and 4 miRNAs(hsa-miR-204, hsa-miR-148b, hsa-miR-618, and hsa-miR-103) as critical transcriptional and post-transcriptional regulators of DEGs.Integrated analyses including Kaplan-Meier survival curves, immune infiltration profiling, and comprehensive mutational analysis demonstrated significant associations with brain metastatic progression in the studied cohort. This study provides novel biomarkers from a unique perspective for the diagnosis, prognosis, and development of molecular-targeted therapies or immunotherapies for brain metastasis in NSCLC.

Furthermore, the release of cytotoxic cargo by degranulation could be induced by stimulation of CD4+ cells in cultures of FL and DLBCL suspensions. In line, the direct cytotoxic capacity of TF K cells against lymphoma cells was demonstrated by killing assays with isolated cells, underscoring their potential as a prospective therapeutic target in lymphoma control.

These CD8+CTLs secrete different cytokines (IFN-γ and IL-10) and cytotoxic molecules (perforin and Gzms), which exert immunoregulatory actions to maintain immune homeostasis. The article concludes with a future perspective and a conclusion section, highlighting the critical need to understand CD8+CTLs' cytotoxic and immunoregulatory functions in maintaining immune homeostasis across various diseases, including those with newly identified roles for CD8+CTLs.