Triple-negative breast cancer survival prediction using artificial intelligence through integrated analysis of tertiary lymphoid structures and tumor budding.

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly heterogeneous and clinically aggressive disease. Accumulating evidence indicates that tertiary lymphoid structures (TLSs) and tumor budding (TB) are significantly correlated with the outcomes of patients who have TNBC, but no integrated TLS-TB profile has been established to predict their survival. The objective of this study was to investigate the relationship between the TLS/TB ratio and clinical outcomes of patients with TNBC using artificial intelligence (AI)-based analysis. METHODS: The infiltration levels of TLSs and TB were evaluated using hematoxylin and eosin staining, immunohistochemistry staining, and AI-based analysis. Various cellular subtypes within TLS were determined by multiplex immunofluorescence. Subsequently, the authors established a nomogram model, conducted calibration curve analyses, and performed decision curve analyses using R software. RESULTS: In both the training and validation cohorts, the antitumor/protumor model established by the authors demonstrated a positive correlation between the TLS/TB index and the overall survival (OS) and relapse-free survival (RFS) of patients with TNBC. Notably, patients who had a high percentage of CD8-positive T cells, CD45RO-positive T cells, or CD20-positive B cells within the TLSs experienced improved OS and RFS. Furthermore, the authors developed a comprehensive TLS-TB profile nomogram based on the TLS/TB index. This novel model outperformed the classical tumor-lymph node-metastasis staging system in predicting the OS and RFS of patients with TNBC. CONCLUSIONS: A novel strategy for predicting the prognosis of patients with TNBC was established through integrated AI-based analysis and a machine-learning workflow. The TLS/TB index was identified as an independent prognostic factor for TNBC. This nomogram-based TLS-TB profile would help improve the accuracy of predicting the prognosis of patients who have TNBC.

Generation of cytotoxic T lymphocytes specific for native or modified peptides derived from the epidermal growth factor receptor pathway substrate 8 antigen.

The ideal tumor antigen for the development of a cancer immunotherapy is one that is expressed only in tumor cells. The epidermal growth factor receptor pathway substrate 8 gene (Eps8) might be an effective antigen for cancer immunotherapy as it is overexpressed in a variety of cancer cells but not in normal tissues. In this study, the potential utility of an Eps8-derived immunotherapy was tested in vitro and in vivo. Three computer-based algorithms were used to design eight Eps8 native epitopes with potentially high binding affinity to the HLA-A2.1 molecule, which is found at a high frequency in the Chinese population. Of these eight, three peptides with a moderate affinity to the HLA-A2.1 molecule were modified at anchor residue positions to achieve stronger immunogenicity. These four modified peptides displayed stronger binding affinity to HLA-A2.1 molecules on T2 cells and a lower dissociation rate. In functional assays with human PBMCs in vitro and in HLA-A2.1/K(b) transgenic mice in vivo, CTLs primed by each native and modified peptide secreted IFN-γ and were toxic to cancer cells from a variety of tissue types in an HLA-A2.1-restricted and Eps8-specific manner. p101-109-2L and p276-284-1Y9V were superior to other modified and native epitopes both in vitro and in vivo. These results indicate that employing the native and modified epitopes identified here in Eps8-based immunotherapy for HLA-A2.1 positive cancer patients may result in efficient anticancer immune responses for diverse tumor types.

Novel oncoprotein EPS8: a new target for anticancer therapy.

EPS8 was first identified as a tyrosine kinase substrate, that plays a role in EGFR-mediated mitogenic signaling. Recent research has shown that EPS8 is overexpressed in most types of cancer, for example breast cancer, colon cancer, cervical cancer and even hematologic malignancies. EPS8 is involved in many signaling pathways related to tumorigenesis, proliferation, migration and metastasis, and is a biomarker for poor prognosis of cancer patients. This review aims to provide a comprehensive picture of the role of EPS8 in cellular processes and its significance to tumorigenesis. Furthermore, this review focuses on the potential role of EPS8 as a therapeutic cancer target.

KIR2DL1-HLA signaling pathway: notable inhibition in the cytotoxicity of allo-NK cell against KG1A cell.

BACKGROUND: KIR2DL1 is an important member of killer cell immunoglobulin-like receptors (KIRs). It recognizes the C2 group of alleles exclusively and delivers signals that inhibit NK cell cytotoxicity. METHODS: In this study, NK cells were isolated by magnetic activated cell sorting (MACS) from peripheral blood of 12 healthy unrelated male donors. Flow cytometry (FCM) was used to evaluate the purity of NK cells and phenotypic KIR2DL1 expression on them. The lysis of KG1A and K562 cells by NK cells was analyzed in the lactate dehydrogenase (LDH) assay to investigate whether KIR2DL1 expression on NK cells would affect the cytotoxicity. RESULTS: Significant differences in KIR2DL1 frequency were noted among the donors (range, 27.14% - 92.49%). NK cells with lower KIR2DL1 expression exerted higher cytolytic activity against KG1A cells, whereas those with higher KIR2DL1 expression exerted significantly lower lysis against KG1A cells (R2 = 0.8169, p < 0.05). CONCLUSIONS: KIR2DL1 expression frequency was negatively correlated with the cytotoxicity of NK cells against KG1A cells. This study discovered that differential KIR2DL1 expression could positively affect the lytic activity of NK cells against KG1A cells, suggesting potential clinical value of KIR2DL1 selection in the treatment of acute myeloid leukemia (AML) patients.

Immunotherapies Targeting CD123 for Blastic Plasmacytoid Dendritic Cell Neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, difficult-to-diagnose, highly aggressive myeloid malignancy with poor prognosis and no standard of care. The interleukin-3 receptor α, or CD123, is highly expressed in patients with myeloid malignancies, particularly acute myeloid leukemia and BPDCN. CD123 is overexpressed on leukemic stem cells compared with normal hematopoietic stem cells, suggesting CD123 as an attractive immunotherapeutic target. To date, multiple CD123-targeted therapeutic avenues have been explored to treat BPDCN and other CD123+ hematologic malignancies. This review summarizes immunotherapies targeting CD123 for the treatment of BPDCN and related neoplasms.

Association between Fas/FasL polymorphism and susceptibility to leukemia: a meta-analysis.

The polymorphisms in Fas/FasL system were proposed to be associated with susceptibility to leukemia, but recent studies reported controversial findings. Hence, we performed a meta-analysis to assess the association between Fas gene polymorphisms and susceptibility to leukemia. We carried out a literature search in PubMed, Embase, Web of Science and CNKI databases for studies on the associations between Fas/FasL gene polymorphisms and susceptibility to leukemia. The associations were assessed by odds ratio (OR) together with its 95% confidence intervals (CIs). 7 literatures and 14 studies with a total of 8787 subjects were eventually included into our meta-analysis. Overall, there was no association between Fas/FasL polymorphisms and susceptibility to leukemia. In subgroup analysis by ethnicity, there was also no association between Fas/FasL polymorphisms and susceptibility to leukemia in Asians and Caucasians. In addition, there was also a significant association between Fas-1377G/A polymorphism and susceptibility to leukemia in ALL patients, the A allele seemed to be a protective factor in ALL risk. In summary, more studies with large sample size are needed to provide further evidence for association between Fas/FasL polymorphisms and susceptibility to leukemia.