Immunological effects of everolimus in patients with metastatic renal cell cancer

Abstract

The mammalian target of rapamycin (mTOR) is a crucial kinase present in all cells. Besides its role in the regulation of cell-growth, proliferation, angiogenesis, and survival of malignant tumors, mTOR additionally plays an important role in immune regulation by controlling the balance between effector T cells and regulatory T cells (Tregs). This critically affects the suppressive state of the immune system. Here, the systemic immunological effects of everolimus treatment were comprehensively investigated in five patients with metastatic renal cell cancer. In this hypothesis generating study, the immunological alterations in circulating immune subsets induced by everolimus included a (non-significant) increase in the frequency of Tregs, a significant increase in monocytic myeloid-derived suppressor cells, a significant decrease in the frequency of immunoregulatory natural killer cells, classical CD141+ (cDC1) and CD1c+ (cDC2) dendritic cell subsets, as well as a decrease in the activation status of plasmacytoid dendritic cells and cDC1. These date indicate that the immunological effects of everolimus affect multiple immune cell subsets and altogether tip the balance in favor of immunosuppression, which can be considered a detrimental effect in the treatment of cancer, and may require combination treatment with agents able to negate immune suppression and boost T cell immunity.

Autologous tumor cell vaccination combined with systemic CpG-B and IFN-α promotes immune activation and induces clinical responses in patients with metastatic renal cell carcinoma: a phase II trial

“…As FoxP3 has also been described to be transiently up-regulated on dividing (activated) effector T cells [ 27 – 29 ], we also analyzed FoxP3 expression within these activated (effector-like) T cells, which we defined as CD4 + CD25 intermediate (CD4 + CD25 int ) cells. For Treg gating procedures, we refer to Huijts et al 2017 [ 30 ].…”

NK Cell-Based Immunotherapy in Renal Cell Carcinoma

“…Specifically, a significant decrease in the frequency of the CD56 bright NK cell subset and the conventional DCs was found, along with an increase in Treg cells and monocyte MDSCs. These data suggest that everolimus may favor immunosuppression and, therefore, that it should be carefully considered in the treatment of these patients [170].…”

“…Moreover, at protein levels, Eomes was highly expressed on circulating NK cells [169], suggesting that NK cells may play a role in the tumor response in RCC patients treated with sorafenib. On the other hand, in patients with metastatic RCC, the systemic effect of the mTOR inhibitor everolimus was shown to induce immunological alterations in circulating immune cells, including NK cells [170]. Specifically, a significant decrease in the frequency of the CD56 bright NK cell subset and the conventional DCs was found, along with an increase in Treg cells and monocyte MDSCs.…”

The Role of Myeloid Derived Suppressor Cells in Urothelial Carcinoma Immunotherapy

“…Elements that drive MDSC development include endoplasmic reticulum stress and the transcription factors STAT3, IRF8 and C/EBP␤ [7,8]. Cancer therapies that are thought to modulate MDSC include tyrosine kinase inhibitors (TKI) such as sunitinib [35][36][37][38][39] and sorafenib; [40][41][42][43][44] vascular endothelial growth factor (VEGF) inhibitors such as bevacizumab; [45] mammalian target of rapamycin (mTOR) inhibitors; [46][47][48][49][50] deacetylase (HDAC) inhibitors; [51,52] fibroblast growth factor receptor (FGFR) inhibitors; [48,53] chemotherapeutic agents such as gemcitabine, [54] 5-fluorouracil (5-FU), [55][56][57][58] and cisplatin; [59] and radiation therapy [39,60]. Clinical trials in bladder cancer that have investigated these agents are presented in Table S1.…”