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

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 Although high-dose interleukin 2 immunotherapy has been superseded as first-line therapy for RCC by promiscuous receptor tyrosine kinase inhibitors (rTKIs) such as sunitinib, sunitinib itself is a potent immunoadjunct in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.

Figure 1

The production of chemokines by tumor and stromal cells and their subsequent binding to chemokine receptors expressed by different immune cells results in the activation and trafficking of these cells into renal tumor tissue initiating events that typically promote tumor progression rather than antitumor immunity. Listed are the various immune regulatory cell types infiltrating the tumor along with the different mechanisms they may utilize, alone or in combination, to impair T cell function and/or promote angiogenesis. Also shown are the infiltrating effector T cells along with possible mechanisms that may lead to T cell anergy.

Figure 2

Neutralization of host GM-CSF potentiates responsiveness of 4T1 tumors to sunitinib. BALB/c mice bearing 10 day s.c. syngeneic 4T1 tumors were treated twice daily with 1 mg sunitinib (“Sunitinib” “Sun” or “Sutent” 50 mg/kg) for 9 days, and variously also received 1 gm anti-GMCSF mAb or isotype control mAb i.p. weekly from day 0 of tumor challenge. Mice were sacrificed on day 20 and tumors analyzed for content of MDSCs and T cells. Bar graphs shows frequency or absolute numbers of MDSC, CD4 and CD8 cells intratumorally. Anti-GMCSF but not ctrl IgG reduced MDSC frequency in conjunction with sunitinib treatment and preserved intratumoral T cells compared to sunitinib treated or sunitinib+Ctrl IgG mice. Line graph shows significant retardation of 4T1 progression for sunitinib+anti-GMCSF therapy vs untreated mice, whereas no significant difference for sunitinib or sunitinib+Ctrl IgG mice vs untreated.