Functionally characterizing the renal cell carcinoma tumor immune microenvironment via patient-derived ex vivo models

Abstract Immune cells in the tumor microenvironment (TME) are attractive therapeutic targets, however their responses to immunotherapy and targeted therapy remain incompletely understood. We developed a patient-derived ex vivo system to profile baseline immune characteristics and model treatment-induced activation at the single-cell level. The model was utilized to study T cell responses to PD-1 blockade and VEGFR inhibition (VEGFRi) in renal cell carcinoma (RCC) patients. The baseline RCC TME was highly infiltrated by T cells, characterized by diverse cytotoxic, memory, exhausted, or regulatory phenotypes. T cells were activated by direct CD3/CD28/CD2 stimulation, upregulating the IFN-gamma, TNF, and IL-2 signaling pathways. However, activation capacity varied noticeably depending on the baseline phenotype. PD-1 blockade induced modest T cell activation, whereas VEGFRi downregulated several immune markers, including signaling pathways and immune activation-related cytokines. Our study reveals the suppressive features of the RCC TME and the challenge of fully overcoming it with PD-1 blockade and VEGFRi.