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. While high dose interleukin-2 immunotherapy has been superseded as first line therapy for RCC by promiscuous receptor tyrosine kinase inhibitors (rTKI) such as sunitinib, sunitinib itself is a potent immunoadjunct in animal tumor models. A reasonable therapeutic goal is to unite anti-angiogenic 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, pancreatic, colon, breast and other solid tumors is large numbers of circulating myeloid-derived suppressor cells (MDSC), and because MDSC elicit regulatory T cells rather than vice versa, gaining control over MDSC is an important initial step in any immunotherapy. While rTKI like sunitinib have a remarkable capacity to deplete MDSC and restore normal T cell function in peripheral body compartments such as the bloodstream and the spleen, such rTKI are only effective against MDSC which are engaged in phosphoSTAT3-dependent programming (pSTAT3+). Unfortunately, rTKI-resistant pSTAT3- MDSC are especially apt to arise within the tumor microenvironment itself, necessitating strategies which do not rely exclusively upon STAT3 disruption. The most utilitarian strategy to gain control of both pSTAT3+ and pSTAT3- MDSC may be to exploit the natural differentiation pathway which permits MDSC to mature into tumoricidal macrophages (TM1) via such stimuli as TLR agonists, IFN-γ and CD40 ligation. Overall, this review highlights the mechanisms of immune suppression employed 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.

The immune response in cancer: from immunology to pathology to immunotherapy

“…In metastatic RCC, sunitinib as monotherapy has shown high objective response rates (up to 50 %) and currently is the first-line treatment option for metastatic RCC patients [79]. In addition to normalizing the tumor vascularization, this drug promotes anti-tumor immunity through different mechanisms [80].…”

Minimal changes in the systemic immune response after nephrectomy of localized renal masses11This work was supported by the University of Iowa Carver College of Medicine/Department of Urology Investigator Start-up Funds, NIH Grant CA181088-01 (to L.A.N.), and NIH Grant CA109446 (to T.S.G.).

“…To evaluate the systemic percentages of these immunosuppressive cells in subjects with clear cell RCC vs. healthy controls, we analyzed 4 different MDSC phenotypes based on recent literature [13,25–27]. We found that MDSC population 1 (HLA-DR neg CD14 + ) was significantly increased in subjects with clear cell RCC relative to healthy controls, in whom this cell population was negligible (Fig.…”

“…MDSC suppress T-cell effector and natural killer cell function and also regulate macrophage cytokine production. Unlike murine MDSC definitions, which are characterized by distinct CD11b + Ly6C + (monocytic) or CD11b + Ly6G + (granulocytic) phenotypes, a number of different MDSC phenotypes have been reported in humans [13,25–27]. However, recent literature indicates that MDSCs express CD14 or CD33 or both and lack HLA-DR [13,15,27,31].…”

“…Phenotypic leukocyte subpopulation analyses were as follows: inflammatory monocytes—CD16 neg /CD14 + PerCP-Cy5.5 and stationary monocytes—CD16 + FITC/CD14 neg . MDSCs were analyzed using 4 definitions, as reported previously [13,25–27]. For MDSC population 1: CD14 + PerCP-Cy5.5/HLA-DR neg APC-Cy7; MDSC population 2: CD33 + BV421/HLA-DR neg APC-Cy7; MDSC population 3: CD14 neg PerCP-Cy5.5/HLA-DR neg APCCy7/CD11b + PE-Cy7; and MDSC population 4: CD11b + / HLA-DR neg /CD33 + /CD14 neg .…”

CXCL10 and CCL2 mRNA expression in monocytes is inversely correlated with the HLA-DR lower fraction of monocytes in patients with renal cell carcinoma

“…Renal cell carcinoma (RCC) is known to be resistant to conventional chemotherapeutic agents and is known to induce an immunosuppressive environment. Although tyrosine kinase inhibitors (TKIs), including sorafenib and sunitinib, are widely utilized for the treatment of patients with metastatic RCC and TKIs are expected to act as adjuvants for immunotherapeutic effects (3,4), the anticancer effects of TKIs may be unable to overcome the immunosuppressive microenvironment of RCC hosts (5).…”