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Spatially informed gene signatures for response to immunotherapy in Melanoma

ABSTRACT: Gene signatures have been shown to predict the response/resistance to immunotherapies but with only modest accuracy. Reduction in this precision might be due to the lack of spatial information which prevents the ability from distinguish tumor from tumor-microenvironment (TME) genes. Here we collected gene expression data spatially from three compartments (CD68+macrophages, CD45+leukocytes and S100+tumor cells) of 59-immunotherapy-treated melanoma specimens using Digital Spatial Profiling-Whole Transcriptome Atlas. We developed a computational pipeline to discover compartment-specific gene signatures and determine if adding spatial information can improve patient stratification. We achieved AUC≥0.90 for CD45, AUC≥0.94 for CD68, and AUC≥0.86 for S100B signatures, whereas AUC≥0.70 for pseudo-bulk () signature. Cross-testing in different compartments (e.g., CD45 signature in CD68 and S100B compartments) showed poor performance indicating compartment-specificity. Our novel spatial S100B signature showed the best performance with AUC≥0.80 in the validation cohort (N=46). Testing our signatures in computationally deconvolved pseudo-compartments revealed lower AUCs. We conclude that the spatially defined compartment signatures utilize tumor and TME-specific information, leading to more accurate prediction of treatment outcome, and thus merit prospective clinical

ORGANISM(S): Homo sapiens unidentified

PROVIDER: GSE233305 | GEO | 2023/05/24

REPOSITORIES: GEO

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Project description:Background: Immune-checkpoint inhibition (ICI) only benefits a subgroup of patients with head and neck squamous cell carcinoma (HNSCC). Several molecular and cellular components of the tumor microenvironment (TME) have been hypothesized to drive either response or resistance. Here, spatially defined whole transcriptome data were analysed in search of associations of compartment-specific gene-signatures with HNSCC immunotherapy outcomes. Methods: Pre-treatment biopsy samples from 50 immunotherapy-treated recurrent or metastatic HNSCC patients as well as 12 matched post-treatment biopsies obtained after 4 weeks of treatment, constructed in tissue microarray format (YTMA496), were included in the study. The GeoMx Human Whole Transcriptome Atlas (NanoString Technologies) assay was performed on samples to allow RNA quantification of 18,677 protein encoding genes, using in situ hybridization, in three molecularly defined tissue compartments; tumor (CK), leukocyte (CD45), macrophage (CD68). Differentially expressed genes (DEGs) (P<0.05) between pre- and post-treatment biopsies in each of the tissue compartments were identified. Next, these DEGs were used as a “biological” filter for the initial 18,677 gene set and analysed using LASSO logistic regression models with the aim to obtain pre-treatment gene expression signatures for best overall response (RECIST 1.1.). The performance of each compartment signature was evaluated using the receiver operating characteristic (ROC) curve and AUCs were calculated for Best Overall Response (BOR) to ICI. Results: A six-gene signature (DDX4, COL17A1, HBA1, MMP1, GPNMB, TTN) in the CD45 compartment presented the highest AUC (0.83), followed by signatures in the CK and CD68 compartments (AUC: 0.72 and 0.68, respectively). Cross-testing of the CD45 signature in the other two compartments, as well as in a third, artificially generated “pseudo-bulk” compartment (all compartments combined), showed poor performance, indicating spatial specificity. Interestingly, the CD45 signature included three extracellular-matrix protein-encoding genes (MMP1, COL17A1, TTN), all associated with resistance (negative coefficients in the BOR model) to ICI. Fibroblast and dendritic cell populations, characterized using the CIBERSORTx gene matrix, were the immune phenotypes most closely associated with the CD45 signature. Conclusions: Our results indicate that CD45 molecular tissue compartment gene expression demonstrates increased association with ICI resistance in HNSCC. Extracellular matrix genes rather than immune-cell related genes dominated the CD45 compartment signature, highlighting the importance of non-immune stromal components within the TME and the importance of the use of spatial information in the understanding of ICI resistance.

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Spatially informed gene signatures for response to immunotherapy in Melanoma

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