The Tumor Immune Microenvironment in Clear Cell Renal Cell Carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer that arises from the cells lining the tubes of the kidney. The tumor immune microenvironment (TIME) of ccRCC is a complex interplay of various immune cells, cytokines, and signaling pathways. One of the critical features of the ccRCC TIME is the presence of infiltrating immune cells, including T cells, B cells, natural killer cells, dendritic cells, and myeloid-derived suppressor cells. Among these cells, CD8+ T cells are particularly important in controlling tumor growth by recognizing and killing cancer cells. However, the TIME of ccRCC is also characterized by an immunosuppressive environment that hinders the function of immune cells. Several mechanisms contribute to the immunosuppressive nature of the ccRCC TIME. For instance, ccRCC cells produce cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), which suppress immune cell activation and promote the differentiation of regulatory T cells (Tregs). Tregs, in turn, dampen the activity of effector T cells and promote tumor growth. In addition, ccRCC cells can express programmed death-ligand 1 (PD-L1), which interacts with the programmed cell death protein 1 (PD-1) receptor on T cells to inhibit their function. In addition, other immune checkpoint proteins, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and lymphocyte activation gene 3 (LAG-3), also contribute to the immunosuppressive milieu of the ccRCC TIME. Finally, the hypoxic and nutrient-poor microenvironment of ccRCC can stimulate the production of immunosuppressive metabolites, such as adenosine and kynurenine, which further impair the function of immune cells. Understanding the complex interplay between tumor cells and the immune system in the ccRCC TIME is crucial for developing effective immunotherapies to treat this disease.

Keywords: TIME; ccRCC; clear cell renal cell carcinoma; mccRCC; metastatic clear cell renal cell carcinoma; renal cancer; tumor immune microenvironment.

Figure 1

Mechanism of action of immune checkpoint inhibition in mccRCC (Adapted from [11,12]). The figure was created using BioRender.com.

Figure 2

Clear renal cell carcinoma CAFs associated. ccRCC is related to a loss of the VHL gene, driving overexpression of HIF-1, and leading to the growth of new blood vessels. CAFs release several factors, such as metalloproteins, that promote invasion and proliferation. CAFs are also involved in inflammation through cytokines and chemokine release. As a result, there is an environment that supports the growth and spread of the tumor. The figure was created using BioRender.com.

Figure 3

ccRCC tumors are both angiogenic and immunogenic. The mechanisms of the immunogenic response of mccRCC with dendritic and T cells and its effect in angiogenesis. Shown are the therapies involving tyrosine kinase and immune check inhibitors. The figure was created using BioRender.com.