618: Costimulatory B7-H1 In Renal Cell Carcinoma Patients: Indicator of Tumor Aggressiveness and Potential Therapeutic Target

Thompson, R. Houston; Gillett, Michael D.; Cheville, John C.; Lohse, Christine M.; Dong, Haidong; Webster, W. Scott; Krejci, Kent G.; Lobo, John R.; Sengupta, Shomik; Chen, Lieping; Zincke, Horst; Blute, Michael L.; Strome, Scott E.; Leibovich, Bradley C.; Kwon, Eugene D.

doi:10.1016/s0022-5347(18)34858-4

Cited by 19 publications

(3 citation statements)

References 26 publications

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“…PD-1 is expressed after T cell activation, and when PD-1 receptors binds to its ligands PD-L1 (B7-H1) or PD-L2, T cell function is blocked (Tang and Heng 2013;Freeman et al 2000); approximately 56 % of RCC tumors have infiltration of PD-1 + T cells, and patients with PD-1 + immune cells were at significant risk of cancer-specific death when compared to PD-1-negative patients (Thompson et al 2007). Additionally, the ligand PD-L1 is known to be expressed on a portion of renal tumors (30 %), and expression of this ligand is associated with poor prognosis (Thompson et al 2004(Thompson et al , 2006. Anti-PD1 antibodies have shown significant efficacy in several tumor types (25 %) including RCC, melanoma, and non-small-cell lung cancer Lipson et al 2013).…”

Section: Checkpoint Inhibitors As Immunotherapymentioning

confidence: 99%

The Role of Inflammation in Kidney Cancer

Chevez

Finke

Bukowski

2014

Advances in Experimental Medicine and Biology

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Renal cell carcinoma (RCC) constitutes more than 90 % of primary kidney tumors with the development of metastatic disease in the lung, bone, liver, and brain. Clear-cell RCC (CCRCC) is the most common histologic form of sporadic kidney cancer where the majority of tumors have inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene resulting in the accumulation of hypoxia-inducible factor (HIF) leading to dysregulation of cell growth and angiogenesis. Understanding of the genetic changes in RCC and the downstream events have led to the development of tyrosine kinase inhibitors (TKI) that target HIF-regulated proteins which currently represents front-line therapy for metastatic disease although resistance develops in most patients overtime. Despite the fact that RCC is an immunogenic tumor, there is mounting evidence that immune cells and inflammatory pathways can enhance tumor growth and immune escape. However, recent studies are beginning to uncover the mechanisms of immune escape in RCC, and the role inflammatory immune cells and cytokines play is this process. These new findings have led to renewed interest in the use of immunotherapy for the treatment of this disease that includes strategies to regulate inflammatory responses. Here, we will discuss the different inflammatory signaling pathways (e.g., VHL, hypoxia, TNF-α, STAT, and TGF-β) and the downstream transcription factors, cytokines, and chemokines involved in tumor development, and disease progression. This will include assessment of the role inflammatory molecules (e.g., pVHL, TGFb, IL6, select chemokines/chemokine receptors) play in promoting cell transformation, survival, proliferation of tumor cells, and metastasis derived from in vitro and in vivo studies. Included is a section on how select inflammatory cells (TAM, MDSC, and neutrophils) promote tumor evasion of immune cells. We also provide examples of molecules/cells that correlate negatively (CXCL12, CXCR4, and MMP, neutrophils, and MDSC) and positively (TH1 cells, IP-10, and MIG) with tumor progression and survival. Finally, there is a discussion of different inhibitors of inflammation that may be useful in the treatment of RCC.

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Section: Checkpoint Inhibitors As Immunotherapymentioning

confidence: 99%

The Role of Inflammation in Kidney Cancer

Chevez

Finke

Bukowski

2014

Advances in Experimental Medicine and Biology

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“…This molecule can interact with PD-1 and CD80 on T cells, thereby inducing apoptosis, anergy or exhaustion of effector T cells [85,86]. In a variety of tumors, expression of PD-L1 is associated with poorer survival [87][88][89][90][91][92][93][94]. Unexpectedly, expression of cell-surface PD-L1 in cervical cancer patients was associated with improved survival [95].…”

Section: Indirect Evasion Of T-cell Mediated Killingmentioning

confidence: 99%

Immunosuppressive Tumor Microenvironment in Cervical Cancer Patients

Piersma

2011

Cancer Microenvironment

105

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Cervical cancer is caused by Human papillomavirus (HPV) in virtually all cases. These HPV-induced cancers express the viral oncogenes E6 and E7 and are therefore potentially recognized by the immune system. Despite the abundant presence of these foreign antigens, the immune system is unable to cope with the tumor. Due to the constant immunological pressure, cervical cancers can evolve different immune evasion strategies, which will be described in the current review. Several approaches for immunotherapy of cervical cancer are currently under development, which aim at inducing strong HPV-specific immunity. Besides the reinforcement of potent anti-tumor immune responses, immunotherapy could also enhance HPV-specific T regulatory cells. Supplementary strategies that neutralize an immunosuppressive milieu may have great potential. These strategies are discussed as well.

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“…32,33 PDL1 expression has been studied in many cancers, with evidence of correlations with clinicopathological features, including survival, in several studies. [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] In ACC, only one study analyzed the prevalence and prognostic value of PDL1 expression 49 in a small series of 28 samples and at the protein level using immunohistochemistry (IHC). Here, we have analyzed PDL1 mRNA expression in 146 clinical ACC samples.…”

Section: Introductionmentioning

confidence: 99%

PDL1 expression is associated with longer postoperative, survival in adrenocortical carcinoma

et al. 2019

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Adrenocortical carcinomas (ACCs) are heterogeneous cancers associated with a very poor prognosis. The improvement of prognostic tools and systemic therapy are urgently needed. Targeting the immune system using checkpoint inhibitors such as PD1/PDL1 inhibitors is an attractive novel therapeutic strategy for poor-prognosis tumors. Multiple clinical trials are ongoing, including in advanced ACC. However, PDL1 expression has been studied in ACC in only one heterogeneous series of 28 clinical samples. Here, we have retrospectively analyzed PDL1 mRNA expression in 146 clinical ACC samples and searched for correlations between expression and biological and clinicopathological data, including post-operative disease-free survival (DFS). PDL1 mRNA expression was heterogeneous across samples. "PDL1-high" tumors were not associated with the classical prognostic variables but were associated with longer DFS in both uni-and multivariate analyses. High PDL1 mRNA expression was associated with biological signs of the cytotoxic local immune response. Supervised analysis between "PDL1-high" and "PDL1-low" tumors identified a robust 370-gene signature whose ontology analysis suggested the existence in "PDL1-high" tumors of a cytotoxic T-cell response, however, associated with some degree of T-cell exhaustion. In conclusion, PDL1 mRNA expression refines the prognostication in ACC and high expression is associated with longer DFS. Clinical validation at the protein level and functional validation are required to fully understand the role of PDL1 in ACC. Reactivation of dormant tumor-infiltrating lymphocytes by PDL1-inhibitors could represent a promising strategy in "PDL1-high" ACCs, supporting the ongoing clinical trials.

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618: Costimulatory B7-H1 In Renal Cell Carcinoma Patients: Indicator of Tumor Aggressiveness and Potential Therapeutic Target

Cited by 19 publications

References 26 publications

The Role of Inflammation in Kidney Cancer

The Role of Inflammation in Kidney Cancer

Immunosuppressive Tumor Microenvironment in Cervical Cancer Patients

PDL1 expression is associated with longer postoperative, survival in adrenocortical carcinoma

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