Despite evidence that antitumor immunity can be protective against renal cell carcinoma (RCC), few patients respond objectively to immunotherapy and the disease is fatal once metastases develop. We asked to what extent combinatorial immunotherapy with Adenovirus-encoded murine TNF-related apoptosis-inducing ligand (Ad5mTRAIL) plus CpG oligonucleotide, given at the primary tumor site, would prove efficacious against metastatic murine RCC. To quantitate primary renal and metastatic tumor growth in mice, we developed a luciferase-expressing Renca cell line, and monitored tumor burdens via bioluminescent imaging. Orthotopic tumor challenge gave rise to aggressive primary tumors and lung metastases that were detectable by day 7. Intra-renal administration of Ad5mTRAIL+CpG on day 7 led to an influx of effector phenotype CD4 and CD8 T cells into the kidney by day 12 and regression of established primary renal tumors. Intra-renal immunotherapy also led to systemic immune responses characterized by splenomegaly, elevated serum IgG levels, increased CD4 and CD8 T cell infiltration into the lungs, and elimination of metastatic lung tumors. Tumor regression was primarily dependent upon CD8 T cells and resulted in prolonged survival of treated mice. Thus, local administration of Ad5mTRAIL+CpG at the primary tumor site can initiate CD8-dependent systemic immunity that is sufficient to cause regression of metastatic lung tumors. A similar approach may prove beneficial for patients with metastatic RCC.

Mycobacterium bovis bacille Calmette–Guerin (BCG) is one of the great success stories of immunotherapy as a treatment for superficial urothelial carcinoma of the bladder. Despite clinical effectiveness in over 50% of patients, the high incidence of local side effects and presence of nonresponders has led to efforts to improve the therapy. Recent advances have suggested a role for neutrophils and TNF-related apoptosis-inducing ligand (TRAIL) in the antitumor inflammatory response. Cell wall components of mycobacteria alone, lowered doses of BCG, and combination with cytokines have been studied as ways to improve the immune response associated with BCG and/or reduce toxicity. This review will discuss the clinical use of BCG, its proposed mechanism of action, and directions of future research to improve efficacy and decrease side effects.

Collagen exposure in tissue activates platelets, initiates wound healing, and modulates adaptive immunity. In this report, data are presented to demonstrate a requirement for platelet-derived CD154 for both collagen-induced augmentation of T-cell immunity and induction of protective immunity to Listeria challenge. Specifically, we demonstrate that Ad5 encoding the membrane-bound form of ovalbumin (Ad5-mOVA) delivered in collagen induces higher ovalbumin-specific cytotoxic T lymphocyte (CTL) activity in a dose-dependent manner compared with Ad5-mOVA delivered in PBS. Increased CTL activity was dependent on the ability of platelets to respond to collagen and to express CD154. Furthermore, mice immunized with low-dose Ad5-mOVA in collagen were able to control a challenge of Listeria monocytogenes recombinant for ovalbumin expression (Lm-OVA), whereas mice immunized with low-dose Ad5-mOVA in PBS were not. These data indicate that in a physiologic setting that mimics wounding, platelets perform a sentinel function when antigen dose is too low to provoke an efficient immune response, and can enhance the generation of antigen-specific CD8 T cells that are functionally relevant to the host. IntroductionBecause pathogens are capable of logarithmic expansion upon host infection, it is critical that both innate and adaptive immunity are initiated without delay to ensure survival. An effective adaptive response is dependent upon efficient activation of innate immunity since antigen presenting cells (APCs) that are not fully activated are poor stimulators of T-or B-cell responses. [1][2][3] However, the initial infection usually involves entry of only a few microbes resulting in a very low antigen dose unlikely to provoke a prompt immune response. To compensate, the immune system has been designed with important activating early signaling components such as the Toll-like receptor (TLR) family, and costimulatory molecules such as CD40 ligand (CD40L, CD154), which help lower the threshold for cellular activation. 4,5 CD154 is a molecule critical to adaptive immunity. It is required for T-dependent humoral responses including affinity maturation, somatic hypermutation, germinal center (GC) formation, and B-cell memory. 6 In addition, there is a role in some models for CD154 in generation of normal CD8 T-cell memory and cross-presentation of class I-restricted antigen. [7][8][9][10][11][12][13] Until recently, functionally relevant expression of CD154 was thought to be restricted to CD4 T cells where its purpose in cellular immunity is to stimulate APCs that in turn potently activate T cells 2 ; however, functional CD154, which was able to generate an inflammatory response from endothelial cells, has also been reported on platelets. 14 The role platelets can play in antimicrobial immunity is well documented. They are activated by and able to engulf bacteria and viruses, release antimicrobial and antifungal proteins, release reactive oxygen species, express TLR, protect against helminth infections, and play a role in modulating ...

Study Type – Prognosis (individual cohort) Level of Evidence 2b What's known on the subject? and What does the study add? RENAL nephrometry is a quantitative, reproducible scoring system that characterizes RENAL masses and standardizes reporting. Previous work has suggested that the system may be useful in predicting outcomes after partial nephrectomy. This study is the first to correlate RENAL nephrometry score with operative approach or risk of complication in patients undergoing either partial or radical nephrectomy. OBJECTIVE To evaluate the utility of the RENAL scoring system in predicting operative approach and risk of complications. The RENAL nephrometry scoring system is designed to allow comparison of renal masses based on the radiological features of (R)adius, (E)xophytic/endophytic, (N)earness to collecting system, (A)nterior/posterior and (L)ocation relative to polar lines. METHODS A retrospective review of all patients at a single institution undergoing radical nephrectomy (RN) or partial nephrectomy (PN) for a renal mass between July 2007 and May 2010 was carried out. Preoperative RENAL score was calculated for each patient. Surgical approach and operative outcomes were then compared with the RENAL score. RESULTS In all, 249 patients underwent either RN (158) or PN (91) with average RENAL scores of 8.9 and 6.3, respectively (P < 0.001). Patients who underwent RN were more likely to have hilar tumours (64% vs 10%, P < 0.001) than patients who underwent PN, but were no more likely to have posteriorly located tumours (50% each). There were more complications among patients with RN (58%) vs patients with PN (42%, P= 0.02). RENAL scores were higher in patients with PN who developed complications than in patients with PN who did not develop complications (6.9 vs 6.0, P= 0.02), with no difference noted among patients with RN developing complications (8.9 vs 8.9, P= 0.99). CONCLUSION The RENAL system accurately predicted surgeon operative preference and risk of complications for patients undergoing PN.

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.