Functionally Characterizing the Renal Cell Carcinoma Tumor-Immune Microenvironment via Patient-Derived Ex Vivo Models

  • Cancer Res Commun. 2026 Feb 1;6(2):402-420. doi: 10.1158/2767-9764.CRC-25-0447.
Neja Sirc  1  2  3 ,  Johannes Smolander  1  2  3  4 ,  Anita N Kumari  1  2 ,  Jianyin Liu  1  2 ,  Moon Hee Lee  1  2  3 ,  Kanerva Lahdensuo  5 ,  Riikka Järvinen  5 ,  Sara V Tornberg  5 ,  Linh Lin  3  4 ,  Hanna K Laitinen  3  4 ,  Jason Theodoropoulos  1  2  3 ,  Jay Klievink  1  2  3 ,  Tuomas Mirtti  3  6  7 ,  Anna S Kreutzman  1 ,  Heidi M Haikala  3  4 ,  Petrus Järvinen  5 ,  Satu Mustjoki  1  2  3 ,  Karita Peltonen  1  2  3
Affiliations
  • 1. Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
  • 2. Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland.
  • 3. iCAN Digital Precision Cancer Medicine Flagship, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
  • 4. HaikaLab Immuno-Oncology Research Group, Translational Immunology Research Program (TRIMM), Research Programs Unit, University of Helsinki, Helsinki, Finland.
  • 5. Abdominal Center, Urology, Helsinki University Hospital, Helsinki University, Helsinki, Finland.
  • 6. Department of Pathology, Research Program in Systems Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
  • 7. Finnish Cancer Institute, Helsinki, Finland.
PMID: 41637441 DOI: 10.1158/2767-9764.CRC-25-0447
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 patients with renal cell carcinoma (RCC). 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-γ, TNF, and IL2 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.

Significance: We developed a patient-derived ex vivo model to study immune cell therapy responses within the TME of RCC. Immune activation toward PD-1 blockade and VEGFRi was attenuated and depended on the immune cell state.

Products