Myeloid suppressor cells with high arginase activity are found in tumors and spleen of mice with colon and lung cancer. These cells, described as macrophages or immature dendritic cells, deplete arginine and impair T cell proliferation and cytokine production. Although arginase activity has been described in cancer patients, it is thought to originate from tumor cells metabolizing arginine to ornithine needed to sustain rapid cell proliferation. The goal of this study was to determine whether myeloid suppressor cells producing high arginase existed in renal cell carcinoma patients. Peripheral blood mononuclear cells from 123 patients with metastatic renal cell carcinoma, prior to treatment, were found to have a significantly increased arginase activity. These patients had a markedly decreased cytokine production and expressed low levels of T cell receptor CD3zeta chain. Cell separation studies showed that the increased arginase activity was limited to a specific subset of CD11b+, CD14-, CD15+ cells with a polymorphonuclear granulocyte morphology and markers, instead of macrophages or dendritic cells described in mouse models. Furthermore, these patients had low levels of arginine and high levels of ornithine in plasma. Depletion of the CD11b+, CD14- myeloid suppressor cells reestablished T cell proliferation and CD3zeta chain expression. These results showed, for the first time, the existence of suppressor myeloid cells producing arginase in human cancer patients. In addition, it supports the concept that blocking arginase may be an important step in the success of immunotherapy.

No abstract

No abstract

Purpose Taxane induced peripheral neuropathy (TIPN) is an important survivorship issue for many cancer patients. Currently, there are no clinically implemented biomarkers to predict which patients might be at increased risk for TIPN. We present a comprehensive approach to identification of genetic variants to predict TIPN. Experimental Design We performed a genome wide association study (GWAS) in 3431 patients from the phase III adjuvant breast cancer trial, ECOG-5103 to compare genotypes with TIPN. We performed candidate validation of top SNPs for TIPN in another phase III adjuvant breast cancer trial, ECOG-1199. Results When evaluating for Grade 3-4 TIPN, 120 SNPs had a p-value <10−4 from patients of European descent (EA) in ECOG-5103. 30 candidate SNPs were subsequently tested in ECOG-1199 and SNP rs3125923 was found to be significantly associated with Grade 3-4 TIPN (p=1.7×10−3; OR=1.8). Race was also a major predictor of TIPN, with patients of African descent (AA) experiencing increased risk of Grade 2-4 TIPN (HR=2.1; p=5.6×10−16) and Grade 3-4 TIPN (HR=2.6; p=1.1×10−11) compared with others. A SNP in FCAMR, rs1856746, had a trend toward an association with Grade 2-4 TIPN in AA patients from the GWAS in ECOG-5103 (OR=5.5; p=1.6×10−7). Conclusion rs3125923 represents a validated SNP to predict Grade 3-4 TIPN. Genetically determined AA race represents the most significant predictor of TIPN.

Addition of tamoxifen to CAF-Z improves outcome for premenopausal node-positive, receptor-positive breast cancer. The role of OA/OS alone or with other endocrine agents should be studied more intensely.