Current Advance of Immune Evasion Mechanisms and Emerging Immunotherapies in Renal Cell Carcinoma

Abstract

Renal cell carcinoma is a highly heterogeneous cancer group, and the complex microenvironment of the tumor provides appropriate immune evasion opportunities. The molecular mechanism of immune escape in renal cell carcinoma is currently a hot issue, focusing primarily on the major complex of histocompatibility, immunosuppressive cells, their secreted immunosuppressive cytokines, and apoptosis molecule signal transduction. Immunotherapy is the best treatment option for patients with metastatic or advanced renal cell carcinoma and combination immunotherapy based on a variety of principles has shown promising prospects. Comprehensive and in-depth knowledge of the molecular mechanism of immune escape in renal cell carcinoma is of vital importance for the clinical implementation of effective therapies. The goal of this review is to address research into the mechanisms of immune escape in renal cell carcinoma and the use of the latest immunotherapy. In addition, we are all looking forward to the latest frontiers of experimental combination immunotherapy.

Keywords: immune checkpoint; immunotherapy; renal cell carcinoma; tumor immune evasion; tumor microenvironment.

Figure 1

A schematic diagram of mechanisms of immune evasion in renal cell carcinoma. (I) Immunosuppressive cells and their secreted cytokines, such as interleukin-10 (IL-10), prostaglandin E2 (PGE2), and transforming growth factor-β (TGF-β) secreted by myeloid-derived suppressor cell (MDSC) and other cells. (II) The interaction of T cells and tumor cells and the mode of action of monoclonal antibodies. (III) Gangliosides secreted by renal cell carcinoma cells promote T cell apoptosis. (IV) The absence of components related to antigen processing leads to a decline in antigen presentation function. RCC, renal cell carcinoma; DC, dendritic cell; NK, natural killer cell; Treg, regulatory T cell; Breg, regulatory B cell; TAM, tumor-associated macrophage; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor-α; HLA, human leukocyte antigen; TAP, transport protein proteins associated with antigen processing; LMP, low molecular weight protein; CD28, cluster of differentistion 28; CTLA-4 (CD152), cytotoxic T-lymphocyte associated protein 4; TCR, T cell receptor; LAG3 (CD223), gene 3 activation of lymphocyte; PD-1 (CD279), programmed cell death protein 1; B7-1/2 (CD80/CD86); MHC, major histocompatibility complex; PD-L1/L2 (CD274/CD273), programmed cell death protein ligand 1/2.

Figure 2

The development history of immunotherapies in renal cell carcinoma. In 1992, interleukin-2 (IL-2) and interferon-α (IFN-α) were used to treat renal cell carcinoma. Then through the era of targeted drug therapy, drugs targeting specific antigen targets and immune checkpoints have shown considerable clinical efficacy. In recent years, the application of combined immunotherapy has improved the remission rate and prolonged survival of patients with renal cell carcinoma. It is hoping that more drugs and combination immunotherapies will appear in the future. HSPPC-96, heat shock protein peptide complex 96; CAR-T, chimeric antigen receptor T cell; CAR-NK, chimeric antigen receptor NK cell.

Figure 3

Immunotherapy strategies in renal cell carcinoma. RCC, renal cell carcinoma; IL-2, interleukin-2; IFN-α, interferon-α; PD-1, programmed cell death protein 1; PD-L1, programmed cell death protein ligand 1; CTLA-4, cytotoxic T lymphocyte antigen 4; VEGF, vascular endothelial growth factor; LAG3, gene 3 activation of lymphocyte; CAR, chimeric antigen receptor.

Figure 4

The treatment process of patients with renal cell carcinoma using dendritic vaccine. First, monocytes were collected and isolated from the peripheral blood of patients with renal cell carcinoma, and immature dendritic cells (DCs) were formed under the induction of granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). Then the immature DCs are fused with the renal cell carcinoma tumor antigens to obtain immature DCs loaded with tumor antigens. After continuing the culture, the mature DC vaccines are obtained and then injected back into the renal cell carcinoma patients.