The receptor tyrosine kinase inhibitor (RTKI) sunitinib is front-line therapy for metastatic mCC (mRCC), yet all patients eventually become resistant to this anti-angiogenic drug. Unlike other RTKIs, sunitinib also prevents RCC-induced accumulation of myeloid derived suppressor cells (MDSC) and normalizes type-1 T cell function. We observed that this remarkable immunomodulatory impact occurs both in patients and animals regardless of whether tumors regress, stabilize or progress during sunitinib therapy. Nevertheless, critical issues remain to be addressed before sunitinib can reach its full therapeutic potential as an immunomodulator, including the capacity of intratumoral MDSC to resist sunitinib, as well as sunitinib's capacity to inhibit dendritic cell (DC) in addition to MDSC accumulation.. The proposed studies will employ several murine tumor models as well as blood and tumor samples from stage IV mRCC patients to investigate sunitinib's immunotherapeutic impacts in both mouse and cancer patients.
Aim 1 will delineate the mechanisms by which sunitinib prevents tumor enhancement of monocytic-MDSC proliferation, neutrophilic-MDSC differentiation, and neutrophilic-MDSC survival.
Aim 1 will also explore the likelihood that sunitinib's blockade of these three steps of MDSC development is the consequence of promiscuous targeting of different RTKs at each step.
Aim 2 will test the mechanism(s) by which MDSC in tumor and bone marrow compartments display distinctive resistance to sunitinib, contrasting to the extreme sunitinib susceptibility observed for MDSC in peripheral compartments such as spleen and blood.. We have tentatively correlated such sunitinib resistance to locally heightened exposure to GM-CSF and/or hypoxia which causes bystander MDSC to develop in a STAT3-independent manner, thus promoting sunitinib resistance and local T cell dysfunction.
Aim 3 will investigate how sunitinib's capacity to inhibit DC as well as MDSC accumulation impacts its use as an immunomodulator in the setting of vaccine and adoptive T cell immunotherapy. We will develop and test immunotherapy strategies which effectively compensate for sunitinib-induced host DC depletion, and which also aim to overcome compartmental MDSC resistance to sunitinib. These studies should provide the necessary mechanistic and technical insights to pave a clear path for future clinical trials that optimize sunitinib's use in combination immunotherapy for multliple tumor types, including those which may not be angiogenically susceptible to sunitinib therapy

Public Health Relevance

This study is an extension of our observation that the anti-angiogenic drug sunitinib (Sutent), which is active in the treatment of kidney cancer, also boosts the immune system by inhibiting cells called myeloid-derived suppressor cells (MDSC). These studies will aim to understand exactly how sunitinib causes improvements in the anti-cancer immune response, how to make sunitinib even more effective against cancers, and how to make sure the immune system is working at its best during sunitinib treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA150959-05
Application #
8606436
Study Section
Special Emphasis Panel (ZRG1-OTC-W (02))
Program Officer
Welch, Anthony R
Project Start
2010-08-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
$465,402
Indirect Cost
$89,891
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Jaini, Ritika; Rayman, Patricia; Cohen, Peter A et al. (2014) Combination of sunitinib with anti-tumor vaccination inhibits T cell priming and requires careful scheduling to achieve productive immunotherapy. Int J Cancer 134:1695-705
Finke, James H; Rayman, Pat A; Ko, Jennifer S et al. (2013) Modification of the tumor microenvironment as a novel target of renal cell carcinoma therapeutics. Cancer J 19:353-64
Finke, James; Ko, Jennifer; Rini, Brian et al. (2011) MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy. Int Immunopharmacol 11:856-61
Raychaudhuri, Baisakhi; Rayman, Patricia; Ireland, Joanna et al. (2011) Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastoma. Neuro Oncol 13:591-9