Tumor Microenvironment Limits Immunotherapy in Kidney Cancer



Understanding why ChRCC is resistant to current immune therapies is crucial for improving treatment options. ChRCC patients have limited effective treatment choices, and poor outcomes with existing therapies. Insights from this study could lead to more effective, tailored treatments for this type of cancer, potentially improving survival rates and quality of life for patients.


The researchers used advanced techniques, such as single-cell RNA sequencing and T-cell receptor profiling, to analyze tumor and normal kidney tissues from patients with ChRCC and related tumors. They examined the genetic and cellular characteristics of these tumors and compared immune cell infiltration in ChRCC with that in other kidney cancer types.

The study identified that ChRCC tumors originate from specific kidney cells called α-intercalated cells. It revealed a significant lack of immune cells, especially CD8+ T cells, in ChRCC tumors. These T cells showed low expression of immune checkpoints, meaning they were less likely to attack cancer cells effectively. Additionally, ChRCC tumors had a downregulation of HLA class I molecules, which are important for immune system recognition of cancer cells.

These findings suggest that ChRCC's immune environment is not conducive to current immune therapies, as the few immune cells present are not specific to the tumor. This immune "cold" environment means that traditional ICI therapies are less effective. The study highlights the need for treatments that can enhance the infiltration and activity of tumor-specific T cells in ChRCC.

Future research should focus on developing therapies that target the specific pathways identified in this study, such as those involved in ferroptosis and mTORC1 signaling. There is also a need to explore treatments that can improve antigen presentation and increase the presence of tumor-specific T cells in ChRCC, potentially making immunotherapies more effective for this type of cancer.


This research was supported by a National Institutes of Health (NIH) grant (P30CA016359). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was provided by a grant from the Department of Defense Early Career Investigator grant (KCRP AKCI-ECI, W81XWH-20-1). Yale University also provided funding and support for this research.