High risk clear cell renal cell carcinoma microenvironments contain protumour immunophenotypes lacking specific...

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Perioperative immune checkpoint inhibitor (ICI) trials for high-risk clear cell renal cell carcinoma (ccRCC) have yielded inconsistent patient outcomes.
• This suggests that the tumor microenvironment (TME) immune cell composition and spatial organization may be unfavorable for ICI therapy.

Purpose of the Study:

• To define the immunophenotypes within the ccRCC TME using spatial transcriptomics.
• To identify predictive immune cell signatures associated with treatment response in ccRCC.

Main Methods:

• Spatial transcriptomics sequencing (ST-seq) was performed on fresh para-tumour (pTME), low-grade (LG), and high-grade (HG) ccRCC tissue samples.
• Immune cell types and states (exhausted/pro-tumour vs. non-exhausted/anti-tumour) were identified using reference single-cell RNA and T-cell receptor sequencing datasets.

Main Results:

• High-grade ccRCC TMEs exhibit abundant exhausted/pro-tumour immune cells without increased expression of common checkpoints (PD-1, PD-L1, CTLA4) or angiogenic genes.
• Distinct HG TME features include pro-tumour monocytes expressing HAVCR2 and LAG3, exhausted CD8+ T cells with stem-like progenitor gene expression, and pro-tumour macrophages/monocytes expressing TREM2.

Conclusions:

• This study provides the largest ST-seq dataset for human ccRCC, revealing exhausted/pro-tumour immunophenotypes in high-risk ccRCC TMEs.
• Despite being immunogenic, HG ccRCC TMEs are characterized by immune cell states that are not favorable for immune checkpoint inhibitor treatment.