Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma

TLDR

Immune checkpoint blockade (ICB) yields durable disease control in a subset of patients with advanced renal cell carcinoma (RCC), yet the mechanisms underlying resistance remain poorly understood. The study aims to characterize single‑cell transcriptomes of cancer and immune cells from metastatic RCC patients before or after ICB exposure. Single‑cell RNA sequencing was performed on these cells to assess transcriptional changes induced by ICB. Single‑cell analysis revealed that responders exhibit cytotoxic T cells with elevated co‑inhibitory receptors and effector molecules, macrophages shift to pro‑inflammatory yet immunosuppressive states, cancer cells bifurcate into angiogenic and immunosuppressive subpopulations linked to PBRM1 mutation, and these signatures associate with survival, demonstrating that ICB remodels the RCC microenvironment and alters cancer‑immune interactions.

Abstract

Immune checkpoint blockade (ICB) results in durable disease control in a subset of patients with advanced renal cell carcinoma (RCC), but mechanisms driving resistance are poorly understood. We characterize the single-cell transcriptomes of cancer and immune cells from metastatic RCC patients before or after ICB exposure. In responders, subsets of cytotoxic T cells express higher levels of co-inhibitory receptors and effector molecules. Macrophages from treated biopsies shift toward pro-inflammatory states in response to an interferon-rich microenvironment but also upregulate immunosuppressive markers. In cancer cells, we identify bifurcation into two subpopulations differing in angiogenic signaling and upregulation of immunosuppressive programs after ICB. Expression signatures for cancer cell subpopulations and immune evasion are associated with PBRM1 mutation and survival in primary and ICB-treated advanced RCC. Our findings demonstrate that ICB remodels the RCC microenvironment and modifies the interplay between cancer and immune cell populations critical for understanding response and resistance to ICB.