Dr Braun on Fundamental Immune Defects in Chromophobe RCC

"In each of the 3 axes needed for an effective T-cell response, there was a severe immune defect within chromophobe RCC."

David A. Braun, MD, PhD, assistant professor of medical oncology, Louis Goodman and Alfred Gilman Yale Scholar, and member of the Center of Molecular and Cellular Oncology at Yale Cancer Center, described findings from a translational study that characterized immune defects in chromophobe renal cell carcinoma (RCC) compared with clear cell RCC.

In this study, Braun and colleagues set out to understand the biology of certain kidney tumors, including chromophobe RCC, and their immune responses.

Results published in the Journal of Clinical Oncology, pointed to 3 fundamental immune defects in chromophobe RCC: markedly reduced T-cell infiltration, phenotypically inappropriate CD8-positive T cells, and a lack of tumor-specific T-cell responses, Braun reported.

Through this analysis, alpha intercalated cells were identified as the cell of origin for chromophobe RCC. In parallel, the study revealed marked downregulation of antigen presentation and mTOR signaling pathways, both of which are essential for initiating antitumor immune responses. Immune profiling demonstrated a substantial scarcity of immune cells in chromophobe RCC tumors relative to clear cell RCC. Moreover, CD8-positive T cells—key effectors in tumor-specific immunity—were particularly underrepresented, he noted.

Among the limited CD8-positive T cells present in chromophobe RCC, most exhibited non-functional phenotypes, lacking expression of immune checkpoint receptors such as PD-1, suggesting limited capacity to respond to checkpoint blockade, Braun c ontinued. These findings were corroborated in analyses of The Cancer Genome Atlas (TCGA) dataset. Further investigation of T-cell clonality and antigen specificity revealed that the few CD8-positive T cells infiltrating chromophobe RCC tumors were predominantly bystanders, with little evidence of tumor-specific activity, he noted

This immune exclusion phenotype distinguishes chromophobe RCC from clear cell RCC and highlights the limited efficacy of existing immunotherapies in this rare histology, Braun stated. The results underscore the urgent need to identify novel therapeutic targets and strategies tailored to the unique immune landscape of chromophobe RCC, he concluded.