Dissecting Treg Heterogeneity in Human Cancer to find Novel Targets of Immunotheraphy

Alvisi, Giorgia (2022). Dissecting Treg Heterogeneity in Human Cancer to find Novel Targets of Immunotheraphy. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.000152d0

Abstract

T cell dysfunction in the tumor microenvironment (TME) mediated by the hyper-activation of inhibitory subpopulations such as regulatory T cells (Treg) represents a major obstacle to effective antitumor immunity and immunotherapy. The molecular mechanisms at the basis of the increased immunosuppressive capacity of Treg cells in the TME are currently not clear. Preclinical data shows that bulk Treg depletion improves T cell infiltration and its antitumor activity but simultaneously results in deleterious autoimmune responses. Targeting hyperactive Treg specifically present in the tumor would improve antitumor immunity while reducing toxicity. To this aim, we developed 30-parameter FACS to profile millions of single T cells from chemotherapy-naïve cancer patients. Computational algorithms applied to single-cell data identified T cell subsets preferentially enriched in tumors compared to adjacent normal lung tissue and peripheral blood. We found that the Interferon regulatory factor 4 (IRF4) defines a novel specific subpopulation of tumor infiltrating
Tregs with superior immunosuppressive capacity. Integration of
transcriptomic data and whole genome binding sites of transcription
factors further revealed that IRF4, either alone or in combination with its partner BATF, directly controlled a molecular program responsible for Treg hyperproliferation and suppressive functions that included CTLA-4, ICOS, TNFRSF9 (4-1BB) and IL1R2. Accordingly, deletion of Irf4 exclusively in Tregs resulted in delayed tumor growth in mice while the abundance of IRF4+ Tregs correlated with poor prognosis in patients with multiple human cancers. We further identify mesenchyme homeobox 1 (MEOX1), a transcription factor novel to Treg biology, as sufficient to reprogram circulating Tregs to a tumor-infiltrating 4-1BB+ phenotype. MEOX1 activity sustains hyper-activated Treg gene expression and immunosuppression by favoring chromatin accessibility at sites regulated by AP-1/IRF4/BATF.
Thus, Interfering with IRF4-dependent molecular program, which is shared by several solid tumors, may represent a novel immunotherapeutic approach capable to block immunosuppression in the tumor microenvironment.

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