1002 The role of functional polymorphism in immune response genes as biomarkers of BCG immunotherapy outcome in bladder cancer: Establishment of a predictive profile

AbstractWith the introduction of multiple new agents, the role of immunotherapy is rapidly expanding across all malignancies. Bladder cancer is known to be immunogenic and is responsive to immunotherapy including intravesical BCG and immune checkpoint inhibitors. Multiple trials have addressed the role of checkpoint inhibitors in advanced bladder cancer, including atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab (all targeting the PD1/PD-L1 pathway). While these trials have demonstrated promising results and improvements over existing therapies, less than half of patients with advanced disease demonstrate clinical benefit from checkpoint inhibitor therapy. Recent breakthroughs in cancer biology and immunology have led to an improved understanding of the influence of the tumor microenvironment on the host’s immune system. It appears that tumors promote the formation of highly immunosuppressive microenvironments preventing generation of effective anti-tumor immune response through multiple mechanisms. Therefore, reconditioning of the tumor microenvironment and restoration of the competent immune response is essential for achieving optimal efficacy of cancer immunotherapy. In this review, we aim to discuss the major mechanisms of immune evasion in bladder cancer and highlight novel pathways and molecular targets that may help to attenuate tumor-induced immune tolerance, overcome resistance to immunotherapy and improve clinical outcomes.

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Immune differentiation regulator p100 tunes NF-κB responses to TNF

10.1101/414425 ◽

2018 ◽

Author(s):

Budhaditya Chatterjee ◽

Payel Roy ◽

Uday Aditya Sarkar ◽

Yashika Ratra ◽

Meenakshi Chawla ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Negative Feedback ◽

Gene Expression Program ◽

Systems Modeling ◽

Immune Response Genes ◽

Noncanonical Pathway ◽

Expression Program ◽

Stimulation Of

SummaryStringent regulation of TNF signaling prevents aberrant inflammation. TNF engages the canonical NF-κB pathway for activating the RelA:p50 heterodimer, which mediates specific expressions of pro-inflammatory and immune response genes. Importantly, the NF-κB system discriminates between time-varied TNF inputs. Negative feedback regulators of the canonical pathway, including IκBα, are thought to ensure transient RelA:p50 responses to brief TNF stimulations. The noncanonical NF-κB pathway controls a separate RelB activity associated with immune differentiation. In a systems modeling approach, we uncovered an unexpected role of p100, a constituent of the noncanonical pathway, in TNF signaling. Brief TNF stimulation of p100-deficient cells produced an additional late NF-κB activity consisted of the RelB:p50 heterodimer, which distorted the TNF-induced gene-expression program. Periodic TNF pulses augmented this RelB:p50 activity, which was reinforced by NF-κB-dependent RelB synthesis. In sum, the NF-κB system seems to engage distantly related molecules for enforcing dynamical and gene controls of immune-activating TNF signaling.

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Role of immune response genes in production of anti-HLA antibodies following transplantation

Human Immunology ◽

10.1016/0198-8859(93)90384-d ◽

1993 ◽

Vol 37 ◽

pp. 101

Keyword(s):

Immune Response ◽

Hla Antibodies ◽

Immune Response Genes

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Role of immune response genes in anti-HLA antibody production in heart allograft recipients

Human Immunology ◽

10.1016/0198-8859(92)90248-l ◽

1992 ◽

Vol 34 (1) ◽

pp. 72

Author(s):

E. Reed ◽

E. Ho ◽

P. McManus ◽

E.A. Rose ◽

N. Suciu-Foca

Keyword(s):

Immune Response ◽

Antibody Production ◽

Heart Allograft ◽

Immune Response Genes ◽

Hla Antibody

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Murine interstitial nephritis. I. Analysis of disease susceptibility and its relationship of pleiomorphic gene products defining both immune-response genes and a restrictive requirement for cytotoxic T cells at H-2K.

Journal of Experimental Medicine ◽

10.1084/jem.155.4.1075 ◽

1982 ◽

Vol 155 (4) ◽

pp. 1075-1085 ◽

Cited By ~ 35

Author(s):

E G Neilson ◽

S M Phillips

Keyword(s):

Immune Response ◽

T Cells ◽

Interstitial Nephritis ◽

Cytotoxic T Cells ◽

Gene Products ◽

Effector Functions ◽

Immune Response Genes ◽

Relationship Of ◽

Cytotoxic Effector

Anti-tubular basement membrance (alpha TBM) disease-producing interstitial nephritis in mice is not dependent on the generation of alpha TBM antibodies. Susceptibility seems to be defined by very private specificities in H-2K. These specificities are pleiomorphic, providing both immune-response genes and identity restrictions for cytotoxic effector functions expressed by a Thy-1.2+, Lyt-2,3+ T cell. These studies establish a role for T cells in the pathogenesis in interstitial nephritis as well as providing further evidence for the role of H-2K in the expression of an autoimmune disease.

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