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

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 2

A subset of prognostic ccRCC DEGs have pan-cancer prognostic potential.

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A subset of prognostic ccRCC DEGs have pan-cancer prognostic potential. ...
(A and B) PCAs nominal derivatives of combined modulation of expression and effects on prognosis to visualize CD8+ and CD19+ DEGs from (A) ptPBLs and (B) TILs with significant gene modulation and effect on prognosis across the 5 cancers tested. Genes on the far left are more highly expressed in normal tissues than tumors and have positive prognostic effects (N/T pos prog), representing agonistic targets. Genes on the far right are more highly expressed in tumors than normal tissues and have negative effects on prognosis (T/N neg prog), representing antagonistic targets. PCAs also illustrate linkage between gene coexpression and cancer types, in which breast cancer (BC) ptPBLs and NSCLC TILs are most related to other cancers. In (A), all ptPBL DEGs are shown. In (B), DEGs unique to CD8+ TILs or CD19+ TIL-Bs are shown. (C) DEGs common to CD8+ TILs and CD19+ TIL-Bs are shown, where dark highlighted gene names represent best antagonistic targets, and green highlighted gene names represent best agonistic targets. (D) Correlograms representing linkage between the 5 cancers from nominal derivatives demonstrating that NSCLC and BC are most related to ccRCC, independently of patient sample number (Spearman method, coexpression coefficient ladder on right). (E) Graph demonstrating similar expression patterns of pan-cancer DEGs and genes representing infiltrating immune cell subsets used: CD45, CD3, CD4, CD8, CD20, CD56, and CD68 across pan-cancers (n = 11,577). (F) Graph demonstrating distributions of relative ratios of 483 agonistic vs. agonistic pan-cancer genes, in which TILs have higher percentages of genes that are lower in tumors and have positive prognostic value. GI, gastrointestinal; OV, ovarian.