Immune Checkpoint Blockade Resistance in Renal Cell Carcinoma: More than One Player

Renal cell carcinoma (RCC) is the most common type of kidney cancer. Immune checkpoint inhibitors have been approved to treat patients with advanced RCC, but patients become resistant over time. The mechanisms driving resistance to immune checkpoint inhibitors are poorly understood. 

In a recent publication, a team of investigators led by Drs. Van Allen and Choueiri used single cell RNA seq technology to study the changes in the tumor and immune system in advanced RCC patients who received immune checkpoint blockade (ICB). They analyzed a total of 34,326 cells covering various cancer and other cell types, collected from eight patients, seven with advanced metastatic RCC and one with localized disease.  

They observed patients who responded to ICB had subsets of cytotoxic CD8+T cells expressing higher levels of co-inhibitory receptors. They also found that the macrophages from ICB responders often expressed pro-inflammatory signature but also upregulated immunosuppressive markers.

In addition, two distinct cancer cell subpopulations (TP1 and TP2) with differing RNA expression patterns were identified in these tumors. Interestingly, the expression pattern of TP1 cells was found to be associated with improved survival with ICB. 

This highlights the importance of studying different immune pathways to get a better understanding of how the changes in RNA expression in immune cells and cancer cells affect response to ICB, and why some patients respond to ICB, while others don’t or ultimately develop resistance. The research in this work was supported in part by the 2015 Kure It-AACR Research Grant awarded to Dr. Van Allen.  

---