Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses

Abstract

IntroductionMetastatic renal cell cancer (RCC) has a very poor prognosis with a median survival of only 6 to 12 months from the time of diagnosis. 1,2 Historically, there were no established effective treatment approaches for metastatic RCC because of its resistance to radiation and chemotherapy. 3 Until recently, cytokine-based immunotherapy using interferon-␣ (IFN-␣) and/or interleukin-2 (IL-2) was the only effective treatment resulting in response rates of 10% to 20%. 4 The understanding of RCC pathogenesis and identification of molecular mechanisms responsible for the malignant transformation and metastatic spread led to the development of drugs that target cancer-specific pathways, such as the PI3K/AKT and Ras/Raf/MAPK pathways. 5 RCC is often associated with up-regulated Raf1, EGFR, and VEGFR activity. 5,6 Furthermore, in a high proportion of RCC, mutational aberrations of the von Hippel-Lindau (VHL) gene were identified. The loss-of-function of this tumor suppressor gene results in an accumulation of hypoxia inducible factor (HIF)-␣ subunits and stimulation of angiogenesis via VEGF-and PDGF-receptors.Consequently, 2 novel tyrosine kinase inhibitors, sorafenib (Bayer HealthCare, Leverkusen, Germany) 5 and sunitinib (Pfizer, New York, NY), were introduced in the treatment of RCC patients.Sorafenib is a multikinase inhibitor initially developed to inhibit the Raf1-kinase pathway. 2 However, besides the RAF/MEK/ERK pathway, sorafenib targets receptor tyrosine kinases (RTKs), such as VEGFR-2 and -3, PDGFR-␤, Flt-3, and c-KIT. 2,7 In several clinical and preclinical trials, sorafenib was revealed to be a promising anticancer therapeutic, which negatively regulates tumor growth, cell proliferation, and angiogenesis 8,9 and additionally induces apoptosis in tumor cells. 10 In December 2005, sorafenib was approved by the FDA for treatment of patients with advanced/ metastatic RCC. In a randomized trial, sorafenib doubled the median duration of progression-free survival up to 24 weeks in patients refractory to or relapsed during cytokine treatment. 2,11,12 Sunitinib inhibits multiple split kinase domain RTKs, including VEGFR-1 and -2, PDGFR-␣ and -␤, c- 7,13 In 2 phase 2 studies, application of sunitinib resulted in response rates up to 40% and in a randomized phase 3 trial it showed an improved response rate and progression-free survival in comparison to 14,15 However, until now the effects of sorafenib and sunitinib on development and function of normal nonmalignant hematopoetic cells have not been evaluated in detail. It is known that PBLs isolated from patients receiving clinically relevant doses of sorafenib show inhibition of ERK phosphorylation on ex vivo PMA stimulation. 16 We therefore analyzed the immunomodulatory functions of these compounds using T cells and monocyte-derived dendritic cells (MDDCs), which were activated with ligands for TLR3 or 4. We found that sorafenib, but not sunitinib, has a detrimental effect on DC phenotype and inhibits cytokine secretion, migration ability, and T-cell stimulator...

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

“…The role of VEGF in the expansion of Tregs within the tumor microenvironment may explain the observation that some antiangiogenic molecules decrease the number of both circularing and intratumoral Tregs in cancer patients [73][74][75][76]. Intriguingly, although all these antiangiogenic molecules efficiently inhibit the VEGF/VEGFR axis, sunitinib appears to be more potent at decreasing the number of Tregs than many other agents including sorafenib, whose Tregmodulatory potential remains matter of debate [75,[77][78][79][80].…”

“…Intriguingly, although all these antiangiogenic molecules efficiently inhibit the VEGF/VEGFR axis, sunitinib appears to be more potent at decreasing the number of Tregs than many other agents including sorafenib, whose Tregmodulatory potential remains matter of debate [75,[77][78][79][80]. Intriguingly, it has been shown that Tregs infiltrating breast carcinoma lesions are capable of promoting the metastatic dissemination of mammary carcinoma cells as they express on their surface the pro-metastatic TNF superfamily member RANKL [40].…”

Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice

“…Sm is a broad-spectrum RTKI that targets VEGFR-1 and -2, CSF1-R, PDGFRα and β, cKIT receptor, and Flt-3 (36) and is approved for use in the treatment of renal cell cancer and imatinib-resistant or -intolerant GIST (37). As reversal of vascular remodeling is a suggested application of Sm (38), we used this drug to evaluate the effects of RTKIs on the development of splenomegaly and the outcome of infection.…”

Dendritic cells in cancer immunotherapy

“…Anti-CTLA-4 antibodies will hopefully be approved soon [100], and can then be systematically tested also in the context of DC vaccines, which will be very interesting given promising observations in previously vaccinated patients [101,102]. Another possibility for ''off label'' use is Sunitinib, which appears to inhibit STAT3 [9], and could be combined with DC vaccination as it does not appear to block DC or antitumor T cells [103,104].…”