Sunitinib pretreatment improves tumor-infiltrating lymphocyte expansion by reduction in intratumoral content of myeloid-derived suppressor cells in human renal cell carcinoma

Cancer Immunol Immunother. 2015 Oct;64(10):1241-50. doi: 10.1007/s00262-015-1735-z. Epub 2015 Jun 24.

Abstract

Targeted therapy with sunitinib, pazopanib or everolimus has improved treatment outcome for patients with metastatic renal cell carcinoma patients (RCC). However, despite considerable efforts in sequential or combined modalities, durable remissions are rare. Immunotherapy like cytokine therapy with interleukin-2, T cell checkpoint blockade or adoptive T cell therapies can achieve long-term benefit and even cure. This raises the question of whether combining targeted therapy with immunotherapy could also be an effective treatment option for RCC patients. Sunitinib, one of the most frequently administered therapeutics in RCC patients has been implicated in impairing T cell activation and proliferation in vitro. In this work, we addressed whether this notion holds true for expansion of tumor-infiltrating lymphocytes (TILs) in sunitinib-treated patients. We compared resected primary RCC tumor material of patients pretreated with sunitinib with resection specimen from sunitinib-naïve patients. We found improved TIL expansion from sunitinib-pretreated tumor digests. These TIL products contained more PD-1 expressing TIL, while the regulatory T cell infiltration was not altered. The improved TIL expansion was associated with reduced intratumoral myeloid-derived suppressor cell (MDSC) content. Depletion of MDSCs from sunitinib-naïve RCC tissue-digest improved TIL expansion, proving the functional relevance of the MDSC alteration by sunitinib. Our in vivo results do not support previous in vitro observations of sunitinib inhibiting T cell function, but do provide a possible rationale for the combination of sunitinib with immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carcinoma, Renal Cell / immunology
  • Carcinoma, Renal Cell / therapy*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Combined Modality Therapy
  • Everolimus
  • Female
  • Humans
  • Immunotherapy*
  • Indoles / administration & dosage
  • Indoles / adverse effects
  • Interleukin-2 / administration & dosage
  • Kidney Neoplasms / immunology
  • Kidney Neoplasms / therapy*
  • Lymphocytes, Tumor-Infiltrating / drug effects*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Male
  • Middle Aged
  • Molecular Targeted Therapy*
  • Myeloid Cells / drug effects*
  • Myeloid Cells / immunology
  • Neoplasm Metastasis
  • Programmed Cell Death 1 Receptor / metabolism
  • Pyrimidines / administration & dosage
  • Pyrimidines / adverse effects
  • Pyrroles / administration & dosage
  • Pyrroles / adverse effects
  • Sirolimus / administration & dosage
  • Sirolimus / adverse effects
  • Sirolimus / analogs & derivatives
  • Sulfonamides / administration & dosage
  • Sulfonamides / adverse effects
  • Sunitinib
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / transplantation
  • Treatment Outcome

Substances

  • Indoles
  • Interleukin-2
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Pyrimidines
  • Pyrroles
  • Sulfonamides
  • pazopanib
  • Everolimus
  • Sunitinib
  • Sirolimus