The tumor microenvironment in renal cell cancer

Abstract

Purpose of review: In addition to the provision of nutrients and growth factors that facilitate tumor cell proliferation and metastasis, the tumor microenvironment (MEV) restricts immune surveillance of tumor-associated antigens and limits the efficacy of immune checkpoint inhibitors (ICIs), tumor vaccines, and other immune therapies. This review will focus on the immunosuppressive mechanisms operative within the tumor MVE of renal cell carcinoma (RCC). Recent findings: Several of the immunosuppressive mechanisms within the tumor MEV have been identified and are potentially druggable. Clinical trials with agents that target several of these inhibitory pathways are currently underway. Summary: Although RCC is one of several tumor types responsive to ICIs, the effectiveness of these agents is likely to be limited by the various tumor-infiltrating bone marrow-derived myeloid cells that comprise the MEV. Several strategies to combat the recruitment of these cells into tumor tissue or to neutralize their immunosuppressive function have shown encouraging results in animal tumor models and clinical trials. Keywords microenvironment (MEV); renal cell carcinoma (RCC); myeloid-derived suppressor cells (MDSC); tumor-associated macrophages (TAM); microvasculature; tumor-infiltrating lymphocytes (TIL); cytotoxic T lymphocytes (CTL); regulatory T cells (Tregs); immune checkpoint inhibitor (ICI); vascular endothelial growth factor (VEGF); hypoxia-inducible factor (HIF); arginase; indoleamine dioxygenase (IDO) Conflicts of interest There are no conflicts of interest.

VISTA: A Mediator of Quiescence and a Promising Target in Cancer Immunotherapy

“…On immune cells in human NSCLC, VISTA expression is significantly higher in CD3 + T cells than in CD68 + macrophages, which is different from most other cancers [33]. This distinction might potentially be attributed to different antibody clones and quantitation methods, or might be due to the lymphocyte-enriched nature of the human NSCLC TME [44], compared with the highly myeloid cell infiltrates in other human cancers such as PDAC, clear-cell renal cell carcinoma (ccRCC), and colorectal carcinoma (CRC) [45][46][47]. Although VISTA can be expressed on tumor cells, the majority of its expression is on immune cells; furthermore, TME factors such as hypoxia can increase the expression of VISTA, potentially promoting immune suppression through VISTA-dependent pathways.…”

Identification of Key Genes of Prognostic Value in Clear Cell Renal Cell Carcinoma Microenvironment and a Risk Score Prognostic Model

“…The TME is a mixture of fluids, stromal cells, immune cells, extracellular matrix molecules, and numerous cytokines and chemokines, coupled with their significant interactions. However, cells and molecules in this environment are in a dynamic state and contribute to tumor immune evasion, tumor growth, and metastasis, thereby showing the evolutionary nature of tumors [ 8 ]. TME-induced metabolic stress on infiltrating immune cells can result in local immunosuppression and limited reinvigoration of antitumor immunity and lead to impaired antitumor immune responses [ 27 ].…”

“…It is widely known that tumor tissues consist of tumor cells as well as tumor-related normal epithelial, immune, stromal cells, and vascular cells [ 7 ]. In ccRCC, cells in the tumor microenvironment (TME) promote growth and metastasis of tumor cells and suppress the immune system via several elaborate mechanisms [ 8 ]. Constituents of the TME include tumor cells, immune cells, and various types of stromal cells; their interactions have a significant effect on treatment response and disease prognosis.…”

Synergies of Antiangiogenic Therapy and Immune Checkpoint Blockade in Renal Cell Carcinoma: From Theoretical Background to Clinical Reality

“…This negative correlation is likely attributed to the high expression of PD-1, CTLA-4, other immune checkpoint proteins on these invading T cells, and the impaired cytolytic function through interaction with other cells in tumor environment, such as myeloid-derived suppressor cells (MDSCs), which proved to suppress T cell and dendritic cell (DC) function ( 34 , 35 ). Indeed, many studies on RCC microenvironment have reported defective T cell with dysfunctional cytotoxicity and ineffective tumor cell killing ( 36 – 39 ).…”