Modification of the tumor microenvironment as a novel target of renal cell carcinoma therapeutics

James H. Finke, Pat A. Rayman, Jennifer S. Ko, Judy M. Bradley, Sandra J Gendler, Peter A Cohen

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

To move forward with immunotherapy, it is important to understand how the tumor microenvironment generates systemic immunosuppression in patients with renal cell carcinoma (RCC) as well as in patients with other types of solid tumors. Even though antigen discovery in RCC has lagged behind melanoma, recent clinical trials have finally authenticated that RCC is susceptible to vaccine-based therapy. Furthermore, judicious coadministration of cytokines and chemotherapy can potentiate therapeutic responses to vaccine in RCC and prolong survival, as has already proved possible for melanoma. Although high-dose interleukin 2 immunotherapy has been superseded as first-line therapy for RCC by promiscuous receptor tyrosine kinase inhibitors (rTKIs) such as sunitinib, sunitinib itself is a potent immunoadjunct in animal tumor models. A reasonable therapeutic goal is to unite antiangiogenic strategies with immunotherapy as first-line therapy for RCC. This strategy is equally appropriate for testing in all solid tumors in which the microenvironment generates immunosuppression. A common element of RCC and pancreatic, colon, breast, and other solid tumors is large numbers of circulating myeloid-derived suppressor cells (MDSCs), and because MDSCs elicit regulatory T cells rather than vice versa, gaining control over MDSCs is an important initial step in any immunotherapy. Although rTKIs like sunitinib have a remarkable capacity to deplete MDSCs and restore normal T-cell function in peripheral body compartments such as the bloodstream and the spleen, such rTKIs are effective only against MDSCs, which are engaged in phospho-STAT3-dependent programming (pSTAT3+). Unfortunately, rTKI-resistant pSTAT3-MDSCs are especially apt to arise within the tumor microenvironment itself, necessitating strategies that do not rely exclusively on STAT3 disruption. The most utilitarian strategy to gain control of both pSTAT3+ and pSTAT3-MDSCs may be to exploit the natural differentiation pathway, which permits MDSCs to mature into tumoricidal macrophages (TM1) via such stimuli as Toll-like receptor agonists, interferon γ, and CD40 ligation. Overall, this review highlights the mechanisms of immune suppression used by the different regulatory cell types operative in RCC as well as other tumors. It also describes the different therapeutic strategies to overcome the suppressive nature of the tumor microenvironment.

Original languageEnglish (US)
Pages (from-to)353-364
Number of pages12
JournalCancer Journal (United States)
Volume19
Issue number4
DOIs
StatePublished - Jul 2013

Fingerprint

Tumor Microenvironment
Renal Cell Carcinoma
Receptor Protein-Tyrosine Kinases
Immunotherapy
Therapeutics
Neoplasms
Immunosuppression
Melanoma
Active Immunotherapy
Myeloid-Derived Suppressor Cells
Toll-Like Receptors
Regulatory T-Lymphocytes
Interferons
Interleukin-2
Ligation
Colon
Breast
Vaccines
Spleen
Animal Models

Keywords

  • dendritic cells
  • immunosuppression
  • kidney cancer
  • myeloid-derived suppressor cells
  • Renal cell carcinoma
  • STAT3
  • STAT5
  • Tregs
  • tumor microenvironment
  • tumor-associated macrophages

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Modification of the tumor microenvironment as a novel target of renal cell carcinoma therapeutics. / Finke, James H.; Rayman, Pat A.; Ko, Jennifer S.; Bradley, Judy M.; Gendler, Sandra J; Cohen, Peter A.

In: Cancer Journal (United States), Vol. 19, No. 4, 07.2013, p. 353-364.

Research output: Contribution to journalArticle

Finke, James H. ; Rayman, Pat A. ; Ko, Jennifer S. ; Bradley, Judy M. ; Gendler, Sandra J ; Cohen, Peter A. / Modification of the tumor microenvironment as a novel target of renal cell carcinoma therapeutics. In: Cancer Journal (United States). 2013 ; Vol. 19, No. 4. pp. 353-364.
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