Biology subjects

Jakola, A. S.

Publications and source records attributed to Jakola, A. S..

3 recordsLinked to original sources

bioRxiv2024

Cellular and molecular events organizing the assembly of tertiary lymphoid structures in glioblastoma

Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates associated with improved prognosis in numerous tumors. To date, their prognostic value in central nervous system cancers and the events underlying their formation remain unclear. Here, we find that TLS correlate with improved survival in glioblastoma patients. Furthermore, combining spatial transcriptomics of human tissues with longitudinal studies in murine glioma, we establish that the assembly of T cell-rich clusters is a prerequisite for the development of canonical TLS, and show that CD4 T cells play a central role in this process. Indeed, we provide evidence that IL7R+CCR7+ Th1 lymphocytes with lymphoid tissue-inducing potential are recruited to TLS nucleation sites, where they can initiate TLS assembly by expressing lymphotoxin {beta}. Our work defines TLS as a potential prognostic factor in glioblastoma and identifies cellular and molecular mechanisms of TLS formation. These findings have broader implications for the development of TLS-inducing therapies for cancer. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/601824v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@78be05org.highwire.dtl.DTLVardef@1037706org.highwire.dtl.DTLVardef@7b64e1org.highwire.dtl.DTLVardef@11bfd5c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Machine learning for cell classification and neighborhood analysis in glioma tissue

Multiplexed and spatially resolved single-cell analyses that intend to study tissue heterogeneity and cell organization invariably face as a first step the challenge of cell classification. Accuracy and reproducibility are important for the down-stream process of counting cells, quantifying cell-cell interactions, and extracting information on disease-specific localized cell niches. Novel staining techniques make it possible to visualize and quantify large numbers of cell-specific molecular markers in parallel. However, due to variations in sample handling and artefacts from staining and scanning, cells of the same type may present different marker profiles both within and across samples. We address multiplexed immunofluorescence data from tissue microarrays of low grade gliomas and present a methodology using two different machine learning architectures and features insensitive to illumination to perform cell classification. The fully automated cell classification provides a measure of confidence for the decision and requires a comparably small annotated dataset for training, which can be created using freely available tools. Using the proposed method, we reached an accuracy of 83.1% on cell classification without the need for standardization of samples. Using our confidence measure, cells with low-confidence classifications could be excluded, pushing the classification accuracy to 94.5%. Next, we used the cell classification results to search for cell niches with an unsupervised learning approach based on graph neural networks. We show that the approach can re-detect specialized tissue niches in previously published data, and that our proposed cell classification leads to niche definitions that may be relevant for sub-groups of glioma, if applied to larger datasets.

bioinformatics↗

bioRxiv2021

Agonistic CD40 antibody therapy induces tertiary lymphoid structures but impairs the response to immune checkpoint blockade in glioma

Gliomas are brain tumors characterized by immunosuppression. Immunostimulatory agonistic CD40 antibodies (CD40) are in clinical development for solid tumors but are yet to be evaluated for glioma. Here, systemic delivery of CD40 led to cytotoxic T cell dysfunction and impaired the response to immune checkpoint inhibitors in preclinical glioma models. This was associated with an accumulation of suppressive CD11b+ B cells. However, CD40 also induced tertiary lymphoid structures (TLS). In human glioma, TLS correlated with increased T cell infiltration indicating enhanced immune responses. Our work unveils the pleiotropic effects of CD40 therapy in glioma, which is of high clinical relevance.

cancer biology↗