Review and prospect of immune checkpoint blockade therapy represented by PD-1/PD-L1 in the treatment of clear cell renal cell carcinoma

Abstract

As a common tumor of the urinary system, the morbidity and mortality related to renal carcinoma, are increasing annually. Clear cell renal cell carcinoma (CCRCC) is the most common subtype of renal cell carcinoma, accounting for approximately 75% of the total number of patients with renal cell carcinoma. Currently, the clinical treatment of ccRCC involves targeted therapy, immunotherapy, and a combination of the two. In immunotherapy, PD-1/PD-L1 blocking of activated T cells to kill cancer cells is the most common treatment. However, as treatment progresses, some patients gradually develop resistance to immunotherapy. Meanwhile, other patients experience great side effects after immunotherapy, resulting in a survival status far lower than the expected survival rate. Based on these clinical problems, many researchers have been working on the improvement of tumor immunotherapy in recent years and have accumulated numerous research results. We hope to find a more suitable direction for future immunotherapy for ccRCC by combining these results and the latest research progress.

Keywords: Immunotherapy; PD-1/PD-L1; RCC.

Figure 1. Mutations in the VHL gene lead to the accumulation of HIF-α protein, which, because HIF-1α is more sensitive to FIH-1 compared to HIF-2α, leads to the accumulation of HIF-2α in cells and eventually to kidney cancer.

Figure 2. CRT translocates from the endoplasmic reticulum to the cell membrane to recruit APCs, a process that is inhibited by downregulation of perk and by CD47 on the cell surface. HSP70 and HSP90 carry tumor antigenic peptides that translocate to the cell membrane, recruit APCs and stimulate DC cells to secrete pro-inflammatory factors.

Figure 3. ATP binds to purinergic receptors on monocytes and stimulates their phenotypic maturation. HMGB1 binds to TLR4 to activate the corresponding signaling pathway. HMGB1 and ATP synergistically induce IL-1b release from DC cells.