RT Journal Article SR Electronic T1 CD40 agonist-induced IL-12p40 potentiates hepatotoxicity JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP e000624 DO 10.1136/jitc-2020-000624 VO 8 IS 1 A1 Caroline Bonnans A1 Graham Thomas A1 Wenqian He A1 Breanna Jung A1 Wei Chen A1 Min Liao A1 Jonathan Heyen A1 Bernard Buetow A1 Smitha Pillai A1 Diane Matsumoto A1 Javier Chaparro-Riggers A1 Shahram Salek-Ardakani A1 Yan Qu YR 2020 UL http://jitc.bmj.com/content/8/1/e000624.abstract AB Background CD40 is a compelling target for cancer immunotherapy, however, attempts to successfully target this pathway have consistently been hampered by dose-limiting toxicity issues in the clinic that prevents the administration of efficacious doses.Methods Here, using cytokine and cytokine receptor depletion strategies in conjunction with a potent CD40 agonist, we investigated mechanisms underlying the two primary sources of CD40 agonist-associated toxicity, hepatotoxicity and cytokine release syndrome (CRS).Results We demonstrate that CD40 agonist -induced hepatotoxicity and CRS are mechanistically independent. Historical data have supported a role for interleukin-6 (IL-6) in CRS-associated wasting, however, our findings instead show that an inflammatory cytokine network involving TNF, IL-12p40, and IFNγ underlie this process. Deficiency of TNF or IFNγ did not influence CD40-induced hepatitis however loss of IL-12p40 significantly decreased circulating concentrations of liver enzymes and reduced the frequency of activated CD14+MHCII+ myeloid cells in the liver, indicating a role for IL-12p40 in liver pathology.Conclusions As clinical research programs aim to circumnavigate toxicity concerns while maintaining antitumor efficacy it will be essential to understand which features of CD40 biology mediate antitumor function to develop both safe and efficacious agonists.