Fig. 8: Hyperactivation of YAP1 in renal epithelial cells results in T cell dysfunction.
From: Targeting the disrupted Hippo signaling to prevent neoplastic renal epithelial cell immune evasion
A Radar plots showing the functional clusters of T cells in renal tissue with or without induction with doxycycline. The molecular features of reference cells are labeled in black. Molecular features of T cell clusters in our control and transgenic animal models are labeled in red. CD8_Teff/mem: CD8+ effector/memory T cells; Tex: CD8+ exhaust T cells; Tpex: CD8+ pro-exhaust T cells; CD8_Early Activ: CD8+ Early active T cells; CD8_Naivelike: CD8+ Naïve like T cells; CD4_Naivelike: CD4+ Naïve-like T cells; Tfh: follicular Helper T cells; Th1: type 1 helper T cells; Treg: Regulatory T cells. B Dynamic alternation of T cell subpopulations in control (CTR), early renal epithelial neoplastic lesions (D7), and pRCC (M4). *: significantly different when compared to CTR. Statistical difference were performed with scCODA with FDR = 0.05. a: p = 0.064818. C–G Notched Box plots (with minima, maxima, center, and percentile, etc.) were generated at single-cell level to demonstrate the upregulation of cell surface immune suppressive molecules in Tex cells (C), apoptosis-associated molecules in tumor-infiltrating T lymphocytes (D), alterations of the intrinsic transcription factors that drive the expression of cell surface immune suppressive molecules (E), upregulation of cell surface immune suppressive molecules in Tfh cells (F), and upregulation of molecules associated with Treg suppression of T effectors (G). CTR: n = 95; D7: n = 199; M4: n = 260. Please note that mice in the M4 group were generated using a low dose/chronic induction protocol in order to avoid acute neoplasia-associated kidney failure. H FACS analyzes showing the impact of MDSC on T cell expansion. T cells were activated with a combination of IL2 (10 ng/ml), anti-CD3 (α-CD3, 1 ug/ml), and anti-CD28 (α-CD28, 1 ug/ml). T Cell expansion in the co-culture was determined by a carboxyfluorescein diacetate succinimidyl ester (CFSE) dilution assay. Representative FACS graphs showing the expansion of Cd4+ T cells (left panel) and Cd8+ T cells (right panel) (both isolated from mouse spleen) co-cultured with or without 1:1 MDSCs (isolated/purified from Pax8-YAPS127A mice) for 72 h. The same amount of bone marrow cells (BMC) was used as negative control. “Non-stimulated”: T cells without stimulation/activation (negative control). “MDSC (or BMC): T = 1: 1”: MDSCs (or BMCs) and activated T cells were cocultured with a ratio of 1:1. Please note that addition of MDSCs, not BMCs, blocked the expansion of activated Cd4+ and Cd8+ T cells in the co-culture system.
