Different Expression Characteristics of LAG3 and PD-1 in Sepsis and Their Synergistic Effect on T Cell Exhaustion: A New Strategy for Immune Checkpoint Blockade

Abstract

The impairment of immunity characterized by T cell exhaustion is the main cause of death in patients with sepsis after the acute phase. Although PD-1 blockade is highly touted as a promising treatment for improving prognosis, the role of PD-1 plays in sepsis and particularly its different roles in different periods are still very limited. A recent study revealed LAG3 can resist the therapeutic effect of PD-1 blockade in tumor, which inspired us to understand their role in sepsis. We enrolled 26 patients with acute sepsis from 422 candidates using strict inclusion criteria. Follow-up analysis revealed that the expression levels of PD-1 were rapidly increased in the early stage of sepsis but did not change significantly as infection continued ( P < 0.05). However, the expression of LAG3 was contrary to that of PD-1. Compared with LAG3 or PD-1 single-positive T cells, T cells coexpressing LAG3 and PD-1 were significantly exhausted ( P < 0.05). The proportion of coexpressing T cells was negatively correlated with the total number of lymphocytes ( r = −0.653, P = 0.0003) and positively correlated with the SOFA score ( r = 0.712, P < 0.0001). In addition, the higher the proportion of coexpressing T cells was, the longer the hospital stay and the higher the mortality. These results showed that LAG3 and PD-1 had a potential synergistic effect in regulating the gradual exhaustion of T cells in sepsis, which seriously affected the clinical prognosis of patients. Therefore, LAG3 and PD-1 double-positive T cells are an important indicator for immunity detection and prognostic evaluation. In the future, precision therapy may pay more attention to the different expression patterns of these two molecules.

Analysis of Co-inhibitory Receptor Expression in COVID-19 Infection Compared to Acute Plasmodium falciparum Malaria: LAG-3 and TIM-3 Correlate With T Cell Activation and Course of Disease

“…Double-positive cells were highly activated compared to their double-negative counterparts and showed increased levels of the transcription factors T-bet and eomes in COVID-19 and malaria. A previous study by Niu et al demonstrated that the expression of PD1 and LAG-3 on T cells in patients with acute sepsis had a regulatory impact on cytokine production ( 64 ). The degree of inhibition was dependent on the expression pattern of PD1 and LAG-3 on T cells.…”

“…The degree of inhibition was dependent on the expression pattern of PD1 and LAG-3 on T cells. In comparison, single-positive PD1 − LAG-3 + T cells showed the highest cytokine production followed by single-positive PD1 + LAG-3 − T cells while double-positive PD1 + LAG-3 + T cells produced the least amount of cytokines ( 64 ).…”

Immune Checkpoints: Novel Therapeutic Targets to Attenuate Sepsis-Induced Immunosuppression

“…Importantly, anti-LAG-3 antibody was administered in a therapeutic manner at 3 h after sepsis induction, which increases the clinical relevance. A recent study by Niu et al shows T cells co-expressing LAG-3 and PD-1 synergistically inhibit CD4 and CD8 T cells, and this correlated with increased length of hospital stay and higher mortality ( 142 ). Interestingly, this study showed that LAG-3 was only significantly elevated at day 5 post sepsis, as compared to PD-1 which was elevated early at 12 h after sepsis, indicating an important role for LAG-3 immunosuppression during progression of sepsis.…”

“…Blocking PD-1/PD-L signaling pathways is protective in two-hit models of CLP-induced bacterial sepsis followed by fungal C. albicans infection ( 38 , 108 , 113 ). Double LAG-3 and PD-1 positive T cells show significant dysfunction and LAG-3 is upregulated later in the course of sepsis progression in patients ( 142 ). 2B4 is implicated in inhibiting the T cell specific responses, thereby compromising host immune responses ( 34 , 35 ).…”

Six-gene Signature Based on Metabolism Is Closely Related to the Prognosis and Immune Infiltration of Patients With Sepsis

“…and Niu et al also observed the opposite expression trend of LAG3 and PD-1 in sepsis and its important role in T cell exhaustion [58]. However, the role of the other immunocheckpoint molecules plays in the immunotherapy of sepsis are still limited and needs to be further explored.…”