Caux, C. | bioRxiv Science

bioRxiv2018

Redefining mesothelioma types as a continuum uncovers the immune and vascular systems as key players in the diagnosis and prognosis of this disease

Malignant Pleural Mesothelioma (MPM) is an aggressive disease related to asbestos exposure, which incidence is expected to increase in the future, and with no effective therapeutic options. We have performed unsupervised analyses of publicly available RNAseq data for 297 MPM. We found that the molecular profile and the prognosis of this disease is better explained by a continuous model rather than by the current WHO classification into the epitheloid, biphasic and sarcomatoid histological types. The main source of variation of this continuum was explained by the immune and vascular pathways, with strong differences in the expression of pro-angiogenic genes and immune checkpoint inhibitors across samples. These data may inform future classifications of MPM and may also guide personalised therapeutic approaches for this disease.\n\nSignificanceMalignant Pleural Mesothelioma (MPM) is an aggressive disease with no effective therapeutic options. Unsupervised transcriptomic analyses of 297 MPM unveiled the vascular and the immune systems as key players in the prognosis of this disease, and identified potential therapeutic approaches for this disease targeting these pathways.

cancer biology↗

bioRxiv2017

A novel combination of cyclophosphamide and anti-ICOS mAb prevents tumor growth by affecting regulatory T cells in mice with a human immune system

Mice reconstituted with a human immune system and bearing human tumors represent a promising model for developing novel cancer immunotherapies. Here, we used mass cytometry and multi-parametric flow cytometry to characterize human leukocytes infiltrating a human breast cancer tumor model in immunocompromised NOD.SCID.{gamma}c-null mice reconstituted with a human immune system and compared it to samples of breast cancer patients. We observed highly activated human CD4+ and CD8+ T cells in the tumor, as well as minor subsets of innate immune cells in both settings. We also report that ICOS+ CD4+ regulatory T cells (Treg) were enriched in the tumor relative to the periphery in humanized mice and patients, providing a target to affect Treg and tumor growth. Indeed, administration of a neutralizing mAb to human ICOS reduced Treg proportions and numbers and improved CD4+ T cell proliferation in humanized mice. Moreover, a combination of the anti-ICOS mAb with cyclophosphamide reduced tumor growth, and that was associated with an improved CD8 to Treg ratio. However, depletion of human CD8+ T cells only marginally affected tumor control whereas depletion of murine myeloid cells abrogated the effect of the combination therapy. Altogether, our results indicate that a combination of anti-ICOS mAb and chemotherapy controls tumor growth in humanized mice and highlight the crucial implication of innate immunity in treatment efficacy, opening new perspectives for the treatment of breast cancer.\n\nOne sentence summaryICOS expressed on Tregs is a promising target to improve tumor immunity in humans\n\nAbbreviations

immunology↗