Failed immune responses across multiple pathologies share pan-tumor and circulating lymphocytic targets
Anne Monette, … , Igor Jurisica, Réjean Lapointe
Anne Monette, … , Igor Jurisica, Réjean Lapointe
Published March 26, 2019
Citation Information: J Clin Invest. 2019;129(6):2463-2479. https://doi.org/10.1172/JCI125301.
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Research Article Immunology Oncology Article has an altmetric score of 46

Failed immune responses across multiple pathologies share pan-tumor and circulating lymphocytic targets

Abstract

Tumor-infiltrating lymphocytes (TILs) are widely associated with positive outcomes, yet carry key indicators of a systemic failed immune response against unresolved cancer. Cancer immunotherapies can reverse their tolerance phenotypes while preserving tumor reactivity and neoantigen specificity shared with circulating immune cells. We performed comprehensive transcriptomic analyses to identify gene signatures common to circulating and TILs in the context of clear cell renal cell carcinoma. Modulated genes also associated with disease outcome were validated in other cancer types. Through comprehensive bioinformatics analyses, we identified practical diagnostic markers and actionable targets of the failed immune response. On circulating lymphocytes, 3 genes (LEF1, FASLG, and MMP9) could efficiently stratify patients from healthy control donors. From their associations with resistance to cancer immunotherapies and microbial infections, we uncovered not only pan-cancer, but pan-pathology, failed immune response profiles. A prominent lymphocytic matrix metallopeptidase cell migration pathway is central to a panoply of diseases and tumor immunogenicity, correlates with multi-cancer recurrence, and identifies a feasible noninvasive approach to pan-pathology diagnoses. The differentially expressed genes we have identified warrant future investigation into the development of their potential in noninvasive precision diagnostics and precision pan-disease immunotherapeutics.

Authors

Anne Monette, Antigoni Morou, Nadia A. Al-Banna, Louise Rousseau, Jean-Baptiste Lattouf, Sara Rahmati, Tomas Tokar, Jean-Pierre Routy, Jean-François Cailhier, Daniel E. Kaufmann, Igor Jurisica, Réjean Lapointe

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Figure 8

Enrichment of disrupted MMP9 pathways in ccRCC patient circulating cells and various cancers.

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Enrichment of disrupted MMP9 pathways in ccRCC patient circulating cells...
(A) PPI network linking pan-cancer proteins from significant MMP-9 pathways-associated ccRCC ptPBL DEGs. DEGs (nodes/circles) and their interactions (edges/lines) are shown in red (high expression) and green (low expression), and gray edges highlight interactions between them (NAViGaTOR v3 and IID v04-2018). Noninteracting proteins are listed on the top right. DEG nodes are colored according to GO Molecular Functions listed in the legend. Larger node circles, represent the high degree of interactions with all other DEGs, and blue DEG names represent centrality of interactors. (B) Pathway enrichment analysis graphs depicting results of pathDIP analysis for MMP-9 pathway interactors from correlation analyses. Upper panel shows significance of enrichment obtained for individual pathways (P value, –log10) adjusted for multiple testing using FDR and Bonferroni methods. Lower bar plot shows overlap between query genes and members of individual pathways. Respective numbers of known and predicted pathway members are distinguished by opacity, and fill color indicates source of given pathway. Plots are restricted to the top 100 most significant (see Supplemental Figure 7A for the full pathways). (C) Tissue-specific disrupted PPI networks among MMP-9 interactors in cancer. Gained and lost MMP-9 PPIs in 13 nonmalignant and pretreatment tumors highlighting its tissue-specific role in cancer, where 106 disrupted MMP-9 PPIs were identified (n = 2801) (see Supplemental Figure 7). A total of 1814 disrupted PPIs were found, 81% of which are disrupted in only 1 or 2 tissues and only less than 5% are present in more than 3 tissues.