Constitutive expression of functional CD40 on mouse renal cancer cells: Induction of Fas and Fas-mediated killing by CD40L

Lee, J. K.; Seki, Naoko; Sayers, Thomas J.; Subleski, Jeffrey; Gruys, Eilene; Murphy, William J.; Wiltrout, Robert H.

doi:10.1016/j.cellimm.2005.08.029

Cited by 20 publications

(17 citation statements)

References 23 publications

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“…It has been reported that CD40-CD40L axis was involved in a series of cell biological activities, such as cancer, cardiovascular disease, immune disorders, and even Alzheimer's disease (9)(10)(11). CD40 was found to be expressed at an up-regulated level in many epithelial cancers (12)(13)(14)(15). Expression of CD40 and CD40L in gastric cancer tissue was positively correlated with lymphatic metastasis and tumor TNM stage (13).…”

Section: Introductionmentioning

confidence: 85%

“…Expression of CD40 and CD40L in gastric cancer tissue was positively correlated with lymphatic metastasis and tumor TNM stage (13). In mouse renal cancer cells, CD40 induced cell killing effect by activating Fas (12). CD40 signaling provides critical functions in stimulating antigen presentation, priming of helper and cytotoxic T-cells and a variety of inflammatory reactions.…”

Section: Introductionmentioning

confidence: 97%

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Expression of the co-signaling molecules CD40-CD40L and their growth inhibitory effect on pancreatic cancer in vitro

Zhao

Fei

et al. 2012

Oncol Rep

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Abstract. We investigated the expression of the co-signalling molecule CD40 in pancreatic cancer and the growth inhibitory effect of the recombinant soluble human CD40 ligand (rshCD40L) in pancreatic cancer cell lines. Twenty-six cases of pancreatic cancer tissues and corresponding paratumoral normal tissues were immunohistochemically analyzed for CD40 expression. The association of CD40 expression with clinicopathological parameters, including clinical stage, pathological grade, invasion and metastasis, were statistically analyzed. The serum sCD40 levels in pancreatic cancer patients were examined by ELISA. The expression of CD40 in the pancreatic cancer cell lines Panc-1, Aspc-1 and Miapaca-2 was examined by RT-PCR and flow cytometry. The growth inhibitory activity of rshCD40L on pancreatic cancer cell lines was determined by MTT assay. Tumor cell apoptosis was detected by TUNEL and Annexin V/ PI double staining method. CD40 was positive both on the membrane and in the cytoplasm of tumor cells, 69.2% (18/26) of the cases were positive for CD40. CD40 expression was significantly higher in pancreatic cancer tissues compared to adjacent normal tissues (P<0.05). High CD40 expression was associated with TNM stage and lymph node metastasis (both P<0.05). Patients with pancreatic cancer have higher serum sCD40L levels (3.53±0.70 ng/ml) compared to healthy subjects (1.81±0.48 ng/ml, P<0.05). rshCD40L significantly inhibited the proliferation of the pancreatic cancer cell lines and induced apoptosis in these cell lines. The co-signaling molecule CD40 is highly expressed in pancreatic cancer tissues and cell lines and rshCD40L is a potential tool for antitumor therapies.

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Section: Introductionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 97%

Expression of the co-signaling molecules CD40-CD40L and their growth inhibitory effect on pancreatic cancer in vitro

Zhao

Fei

et al. 2012

Oncol Rep

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“…A strategy to target RCC with anti-CD70 antibody-drug conjugates has been proposed on the basis of this evidence [167]. Expression of CD40 is increased in both the vasculature and tumor cells of renal cell carcinoma patients [169,170], and stimulation with CD40L results in increased tumor cell Fas expression and death [169]. Similarly, in a murine RCC model, the combination of CD40 stimulation and IL-2 was found to be superior to either agent alone [171].…”

Section: Evidence From Renal Cell Carcinomamentioning

confidence: 97%

Costimulation, Coinhibition and Cancer

Inman

Frigola

Dong³

et al. 2007

CCDT

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The immune system is an important defense mechanism against cancer and is often dysfunctional in patients with malignancies. The central regulator of the anti-cancer adaptive immune response is the T lymphocyte. T lymphocyte activation requires the completion of a carefully orchestrated series of specific steps that can be preempted or disrupted by any number of critical events. Particularly important is the provision of a costimulatory signal, the binding of accessory molecules on the antigen presenting cell to receptors on the T lymphocyte. Though costimulatory signals were traditionally envisioned as T lymphocyte-activating events, recent discoveries have highlighted their duality: they can be either stimulatory (costimulation) or inhibitory (coinhibition). In this article we review costimulation and coinhibition as potential targets for cancer therapy. We begin by presenting a general framework for thinking about the immune system in the context of cancer. Our discussion then bridges the various aspects of immune dysfunction seen in cancer with the presence of coinhibitory (ex: PD-1, PD-L1, CTLA-4, BTLA) and costimulatory (ex: CD28, ICOS, 4-1BB, CD40, OX40, CD27) signaling. Lastly, we develop a model of cancer-related immune dysfunction that parallels the concept of immunoediting. Throughout the article we emphasize clinically relevant research often applicable-but not limited-to the example of renal cell carcinoma.

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“…It is tempting to speculate that the limited efficacy of ␣CD40 is due to an inability to overcome local regulatory mechanisms within the tumor microenvironment that ultimately allow the tumor to escape immune control. Nevertheless, CD40 is an attractive therapeutic target because, in addition to its ability to stimulate immune responses, its ligation by CD40 ϩ tumors induces cytokine production (12) and enhances Fas-mediated tumor apoptosis (34). While ongoing trials involving agonistic CD40 antibodies continue to provide important insights into the cellular responses to developing tumors in vivo, we believe that our results support the development of IL-2/␣CD40 or IL-15/␣CD40 combination therapy for the improved treatment of solid tumors, including RCC.…”

Section: Discussionmentioning

confidence: 99%

Successful immunotherapy with IL-2/anti-CD40 induces the chemokine-mediated mitigation of an immunosuppressive tumor microenvironment

Weiss

Back

Scarzello

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Many strategies for cancer treatment use combinations of immunotherapeutic agents for enhanced anti-tumor responses. However, these approaches are often complicated by a need to overcome tumor-induced immune suppression in the tumor microenvironment. In this regard, T regulatory (Treg) cells and myeloid-derived suppressor cells (MDSC) have been identified as functional suppressor cells within tumors (1, 2). The most effective immunotherapeutic regimens are likely to consist of agents that restructure, within the tumor microenvironment, the composition of tumor-infiltrating leukocytes away from these inhibitory elements in favor of effector cells, such as NK cells and CD8 ϩ T cells.Chemokine expression can regulate the polarization of immune responses (3). For example, CXCR3 and CCR5 are preferentially expressed on Th1 T cells and M1 macrophages and their respective ligands are associated with enhanced cellmediated immune responses (3-5) and favorable prognosis in human RCC (5, 6). Another chemokine, monocyte chemoattractant protein (MCP)-1 activates macrophages for enhanced anti-tumor activities (7), however MCP-1 expression is also associated with the recruitment of mononuclear cells capable of producing tumor promoting factors (8, 9), as well as MDSC that contribute to tumor progression through the inhibition of effector cell functions (8, 10).We reported previously that IL-2 and agonistic antibody to CD40 (␣CD40) synergize for the regression of metastatic tumors in mice (11). Although we identified CD8 ϩ T cells and host IFN␥ expression as critical components of this therapeutic approach (11), the specific mechanisms underlying the IL-2/␣CD40 synergistic anti-tumor responses within the microenvironment remain unclear. We demonstrate in a murine model of metastatic renal cancer that ␣CD40 may be limited by its dependency upon MCP-1 and an inability to remove Tregs and MDSC specifically from within the tumor microenvironment, allowing for eventual tumor progression. In contrast, synergistic anti-tumor responses and protection achieved by IL-2/␣CD40 are associated with the expression of Th1 chemokines that are associated with favorable prognosis in RCC (5, 6), an augmentation of effector leukocytes and concomitant removal of suppressive cells specifically within the tumor microenvironment. Results CCR2 Expression Is Required for ␣CD40, but Not IL-2/␣CD40 MediatedAnti-Tumor Responses. Our previous study showed that IL-2/ ␣CD40 exhibited strong synergy for treatment of established metastatic tumors in mice, as compared to IL-2 or ␣CD40 as single agents (11). Furthermore, we found that ␣CD40 treatment of Renca-bearing mice induced significant reduction in tumors in association with high levels of systemic MCP-1 levels, suggesting a possible role for MCP-1 in leukocyte recruitment into tumors and CD40-dependent anti-tumor effects (12). To determine the relative contribution of MCP-1 to the ␣CD40-and IL-2/␣CD40-mediated anti-tumor responses, we compared tumor outcomes in treated WT and mice deficient in CCR2, the rec...

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Constitutive expression of functional CD40 on mouse renal cancer cells: Induction of Fas and Fas-mediated killing by CD40L

Cited by 20 publications

References 23 publications

Expression of the co-signaling molecules CD40-CD40L and their growth inhibitory effect on pancreatic cancer in vitro

Expression of the co-signaling molecules CD40-CD40L and their growth inhibitory effect on pancreatic cancer in vitro

Costimulation, Coinhibition and Cancer

Successful immunotherapy with IL-2/anti-CD40 induces the chemokine-mediated mitigation of an immunosuppressive tumor microenvironment

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