Profiling the immune cell repertoire of clear cell renal cell carcinoma patients as a potential factor influencing immunotherapy response
Clear cell renal cell carcinoma (ccRCC) accounts for approximately 70% of the 400,000 newly-diagnosed kidney cancers each year worldwide. Immunotherapy (IO) is a common treatment for ccRCC that works by enhancing the patient’s immune system to recognize and target cancer cells. However, a subset of ccRCC patients do not respond to immunotherapy treatment. Here, we sought to evaluate the immune cell composition of ccRCC tumors from patients treated with IO to identify potential factors distinguishing patients who respond to IO treatment from those who do not respond. Tumor samples were collected prior to immunotherapy treatment from 82 patients with metastatic ccRCC seen at City of Hope. 52 patients received IO as their first line of treatment and 30 patients received IO as their second line of treatment. Clinical bulk whole transcriptome sequencing was performed at Ashion Analytics (Phoenix, AZ) as part of routine clinical management for these patients. First, we analyzed the immune cell infiltration profiles of these ccRCC tumors using TIMER2.0. Across the full cohort, there was no significant difference in the abundance of all six immune cell types between patients who responded and who did not respond to IO treatment. However, within patients who received IO as their first-line therapy, there was a significant increase in CD8+ T cells in non-responders (p=0.0344, Welch’s t-test). This finding is consistent with prior research in other ccRCC cohorts correlating increased CD8+ T cell abundance with poor prognosis and immune evasion. Next, we analyzed the T cell receptor (TCR) repertoire within the tumors using MiXCR and Immunarch. There was no significant difference in TCR diversity or clonality between responders and non-responders. Similarly, Kaplan Meier survival curves of first-line patients, when split by median diversity and median clonality, showed no significant difference in progression-free survival time. Together, these data demonstrate that treatment-naive ccRCC tumors have increased CD8+ T cell abundance in tumors that do not respond to immune checkpoint inhibitors. This association is not seen in patients who receive IO therapy as second-line treatment, suggesting the immune profiles in these tumors and the molecular correlates of IO response may change throughout the course of the disease. Additional features, together with immune cell composition, should be considered when evaluating biomarkers of IO response in ccRCC.