Blocking Neuronal Signaling to Immune Cells Treats Streptococcal Invasive Infection.

The nervous system, the immune system, and microbial pathogens interact closely at barrier tissues. Here, we find that a bacterial pathogen, Streptococcus pyogenes, hijacks pain and neuronal regulation of the immune response to promote bacterial survival. Necrotizing fasciitis is a life-threatening soft tissue infection in which "pain is out of proportion" to early physical manifestations. We find that S. pyogenes, the leading cause of necrotizing fasciitis, secretes streptolysin S (SLS) to directly activate nociceptor neurons and produce pain during infection. Nociceptors, in turn, release the neuropeptide calcitonin gene-related peptide (CGRP) into infected tissues, which inhibits the recruitment of neutrophils and opsonophagocytic killing of S. pyogenes. Botulinum neurotoxin A and CGRP antagonism block neuron-mediated suppression of host defense, thereby preventing and treating S. pyogenes necrotizing infection. We conclude that targeting the peripheral nervous system and blocking neuro-immune communication is a promising strategy to treat highly invasive bacterial infections. VIDEO ABSTRACT.

Clinical outcome of post-chemotherapy retroperitoneal lymph node dissection in metastatic nonseminomatous germ cell tumour: A systematic review.

Post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) is an important element of the management of patients with residual tumour after chemotherapy for disseminated nonseminomatous germ cell tumour (NSGCT). This is a challenging procedure and the outcome varies widely between institutions. There is much debate concerning the anatomical extent of the dissection and the literature is conflicting regarding the outcome of this procedure. In this systematic review we aim to summarise the literature on the relapse rate of PC-RPLND. We performed a search of the literature of the PubMed/MEDLINE and Embase databases, in accordance with the PRISMA guidelines. Studies reporting on the relapse rate of PC-RPLND in NSGCT patients with residual tumour were eligible for inclusion. We calculated the weighted average relapse rates of included studies and assessed the risk of bias using the Newcastle-Ottawa scale. A total of 33 studies, reporting on 2,379 patients undergoing open PC-RPLND (O-RPLND) and 463 patients undergoing minimally invasive PC-RPLND (MI-RPLND) were included. The weighted average relapse rates were 11.4% for O-RPLND, and 3.0% for MI-RPLND. The rates of retroperitoneal relapse were 4.6% and 1.7% after O-RPLND and MI-RPLND, respectively. For O-RPLND specifically, the average retroperitoneal relapse rate was 3.1% after modified dissection and 6.1% after bilateral dissection. We conclude that modified template dissection is oncologically safe in carefully selected patients. Minimally invasive procedures are feasible but long-term data on the oncological outcome are still lacking. PC-RPLND is a complex and challenging procedure, and patients should be treated at high-volume expert centres.

Nedd4-Binding Protein 1 and TNFAIP3-Interacting Protein 1 Control MHC-1 Display in Neuroblastoma.

: Neuroblastoma is the second most common tumor in children. The cause of neuroblastoma is thought to lie in aberrant development of embryonic neural crest cells and is accompanied by low MHC-1 expression and suppression of the NF-κB transcription factor, thereby gearing cells toward escape from immunosurveillance. Here, we assess regulation of the MHC-1 gene in neuroblastoma to enhance its immunogenic potential for therapeutic T-cell targeting. A genome-wide CRISPR screen identified N4BP1 and TNIP1 as inhibitory factors of NF-κB-mediated MHC-1 expression in neuroblastoma. Patients with advanced stage neuroblastoma who expressed high levels of TNIP1 and N4BP1 exhibited worse overall survival. Depletion of N4BP1 or TNIP1 increased NF-κB and MHC-1 expression and stimulated recognition by antigen-specific CD8+ T cells. We confirmed that TNIP1 inhibited canonical NF-κB member RelA by preventing activation of the RelA/p50 NF-κB dimer. Furthermore, N4BP1 inhibited both canonical and noncanonical NF-κB through binding of deubiquitinating enzyme CEZANNE, resulting in stabilization of TRAF3 and degradation of NF-κB-inducing kinase NIK. These data suggest that N4BP1/CEZANNE or TNIP1 may be candidate targets for immunotherapy in neuroblastoma tumors and should lift NF-κB suppression, thereby triggering increased peptide/MHC1-mediated tumor reactivity to enhance therapeutic T-cell targeting. SIGNIFICANCE: Aberrant regulation of NF-κB and MHC-1 in neuroblastoma tumors provides new targets for immunotherapeutic approaches against neuroblastoma.