Immune checkpoint inhibitors for the treatment of sepsis:insights from preclinical and clinical development.

It is now well established that sepsis induces a state of acquired immunosuppression, with an increased risk of secondary infections that contributes to patients' worsening. Thus, tackling sepsis-induced immunosuppression represents a promising perspective. Of mechanisms responsible for sepsis-induced immunosuppression, the increased expression of co-inhibitory receptors such as PD-1, CTLA4, TIM-3, LAG-3, or BTLA and their ligands recently received considerable interest since their inhibition, thanks to the so-called checkpoint inhibitors (CPI), provided astonishing results in cancer by rebooting immune functions. This review reports on the first landmarks of these molecules in sepsis. Preclinical results are positive and the first human early phase clinical trials showed a beneficial effect on immunological functions and/or markers and suggested that tolerance of CPIs side effects, mainly auto-immune disorders, is acceptable in sepsis. Elsewhere, in some specific severe ICU infections such as fungal infections, preliminary convincing case reports have been published. Overall, the first results regarding CPIs in sepsis appear encouraging. However, further efforts are warranted, especially in defining the right patients to be treated (i.e. in an individualized approach) and establishing the optimal time to start an immune restoration. Larger trials are now mandatory to confirm CPIs' potential in sepsis.