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.).

Abstract

Objectives Renal cell carcinoma (RCC) is an immunogenic tumor, and multiple immunostimulatory therapies are in use or under development for patients with inoperable tumors. However, a major drawback to the use of immunotherapy for RCC is that renal tumors are also immunosuppressive. As a result, current immunotherapies are curative in <10% of patients with RCC. To better understand the systemic immune response to RCC, we performed a comprehensive examination of the leukocyte and cytokine/chemokine composition in the peripheral blood of patients with localized clear cell renal tumors pre- and post-nephrectomy. Methods and materials Peripheral blood samples were taken from 53 consented subjects with renal masses before cytoreductive nephrectomy and again at clinic visits approximately 30 days after nephrectomy. Samples were also obtained from 10 healthy age- and gender-matched controls. Blood samples from clear cell RCC subjects were analyzed by multi-parameter flow cytometry to determine leukocyte subset composition and multiplex array to evaluate plasma proteins. Results Pre-nephrectomy, clear cell tumors were associated with systemic accumulations of both “exhausted” CD8+ T cells, as indicated by surface BTLA expression, and monocytic CD14+HLA-DRnegCD33+ myeloid-derived suppressor cells (MDSC). Subjects with T3 clear cell RCC also had a unique pro-tumorigenic and inflammatory cytokine/chemokine profile characterized by high serum concentrations of IL-1β, IL-2, IL-5, IL-7, IL-8, IL-17, TNF-α, MCP-1 and MIP-1β. At an early post-nephrectomy time point (~30 d), we found the systemic immune response to be largely unaltered. The only significant change was a decrease in the mean percentage of circulating BTLA+CD8+ T cells. All other cellular and soluble immune parameters we examined were unaltered by the removal of the primary tumor. Conclusions In the first month following surgery, nephrectomy may relieve systemic CD8 T cell exhaustion marked by BTLA expression, but continuing inflammation and MDSC presence likely counteract this positive effect. Future determination of how this systemic immune signature becomes altered during metastatic progression could provide novel targets for neoadjuvant immunotherapy in RCC. r 2014 Elsevier Inc. All rights reserved.

Myeloid-Derived Suppressor Cell Subset Accumulation in Renal Cell Carcinoma Parenchyma Is Associated with Intratumoral Expression of IL1β, IL8, CXCL5, and Mip-1α

“…Similarly, high serum concentrations of IL-1β and MCP-1 have been described in larger cohorts of RCC patients (57), and IL-1β levels have been shown to be an independent risk factor for increased risk of recurrence and decreased overall survival in limited stage RCC (61). …”

Obesity Triggers Enhanced MDSC Accumulation in Murine Renal Tumors via Elevated Local Production of CCL2

“…Previous studies by our group and others have shown that CCL2 concentrations are elevated in the serum of RCC patients [ 18 , 30 ], and that CCL2 is produced at high levels by the tumor-associated macrophages that infiltrate human renal tumors [ 31 ]. Our murine results agree with these findings and suggest that additional cell populations should be examined in human renal tumors for their production of CCL2.…”

“…MDSCs are immature, myeloid-lineage cells that are recruited to solid tumors by local production of pro-inflammatory cytokines and chemokines [ 13 – 15 ]. Numerous studies have shown that MDSC are key contributors to tumor-associated immune suppression, and we and others have identified them in the peripheral blood and tumors of human subjects with RCC [ 16 – 18 ].…”

Tumor-induced myeloid dysfunction and its implications for cancer immunotherapy

“…The advent of multi-color flow cytometry has allowed for a more comprehensive analysis and identification of specific cellular subsets/phenotypes. Using phenotypic panels shown in Table 1, increased frequencies of at least one ‘immature’ or ‘suppressive’ myeloid subset in the peripheral blood has been identified in patients with melanoma [16–22], sarcoma [21,23,24], head and neck cancer [21,25–28], brain tumors [22,24,29], thyroid cancer [30], lung cancer [21,25,26,31–38], breast cancer [21,25,30,31,39–41], cervical and ovarian cancer [24,31], renal cell carcinoma [22,24,42–45], prostate cancer [46,47], hepatocellular carcinoma [31,48–50], and gastrointestinal cancers [20–22,26,30,31,46,50–55] (including esophagus, stomach, pancreas, bladder/urinary tract, and colorectal cancer) compared to healthy controls or patients with other non-malignant disorders. Atypical myelopoiesis has also been described in hematologic malignancies, including multiple myeloma[56], chronic lymphocytic leukemia[24], mantle cell lymphoma[57], B cell lymphoma[24], and acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) [58,59].…”

“…‘Conventional’ therapies have shown transient decreases in myeloid cell populations following treatment, including surgical resection [46] or radiotherapy [104], but this may not be consistent across tumor types [42,46]. Some studies have assessed myeloid cells following conventional chemotherapy [105].…”