Jean‐Ehrland Ricci

Treatment with immune checkpoint inhibitors (ICIs) is frequently associated with immune‐related adverse events (irAEs). A new study identified an interleukin 7 (IL‐7) allelic variant—rs16906115—as a major risk factor for the development of ICI‐associated irAEs. This association is of great significance as it indicates that germline genetic variants influence the occurrence of irAEs, thus opening a new avenue for identifying high‐risk patients to enable better management of ICI therapy and associated irAEs.

Depletion of circulating asparagine with l -asparaginase (ASNase) is a mainstay of leukemia treatment and is under investigation in many cancers. Expression levels of asparagine synthetase (ASNS), which catalyzes asparagine synthesis, were considered predictive of cancer cell sensitivity to ASNase treatment, a notion recently challenged. Using [U- 13 C 5 ]- l -glutamine in vitro and in vivo in a mouse model of B cell lymphomas (BCLs), we demonstrated that supraphysiological or physiological concentrations of asparagine prevent de novo asparagine biosynthesis, regardless of ASNS expression levels. Overexpressing ASNS in ASNase-sensitive BCL was insufficient to confer resistance to ASNase treatment in vivo. Moreover, we showed that ASNase’s glutaminase activity enables its maximal anticancer effect. Together, our results indicate that baseline ASNS expression (low or high) cannot dictate BCL dependence on de novo asparagine biosynthesis and predict BCL sensitivity to dual ASNase activity. Thus, except for ASNS-deficient cancer cells, ASNase’s glutaminase activity should be considered in the clinic.