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

Abstract

Introduction Sepsis represents one-fifth of all deaths worldwide and is associated with huge costs. Regarding disease progression, 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. Areas covered Of mechanisms responsible for sepsis-induced immunosuppression, the increased expression of co-inhibitory receptors (aka immune checkpoint) 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. We introduce them in terms of basic immunology in line with sepsis pathophysiology both in experimental models and observational works and assess the first human clinical studies. Expert opinion Preclinical results are positive and the first human clinical trials, although currently limited to the early phase, 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 infections leading to ICU admission (or occurring during ICU stay), 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.