New emerging targets in cancer immunotherapy: the role of LAG3

Abstract

The success of immunotherapy in many disease entities is limited to a specific subpopulation of patients. To overcome this problem, dual blockade treatments mainly against cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed cell death receptor (ligand) 1 (PD-(L)1) axis were developed. However, due to high toxicity rates and treatment resistance, alternative pathways and novel strategies were desperately needed. Lymphocyte-associated gene 3 (LAG3) represents an inhibitory receptor, which is mainly found on activated immune cells and involved in the exhaustion of T cells in malignant diseases. Its co-expression with other inhibitory receptors, particularly with PD-1 leads to an extensive research on the blockade of LAG3 and PD-1 in preclinical settings. Interestingly, several in-vivo approaches demonstrated a highly significant clinical benefit under dual blockade, whereas the efficacy was very low in case of single agent targeting. Moreover, human tumour tissues showed co-expression of LAG3 and PD-1 in infiltrated lymphocytes, which again generated a rationale for blocking these both molecules in clinical settings. The ongoing clinical studies mainly use dual blockage of LAG3/PD-1, which demonstrated promising survival benefits and long duration of response rates. The following review focuses on the biological background and rationale of combining LAG3 with other agents and serves as an update on the state of clinical research on LAG3 targeting.

Sex-associated molecular differences for cancer immunotherapy

“…We observed an unexpected divergent pattern of sex-associated differences across different cancer types, especially the opposite pattern between patients with melanoma and lung cancer. Our analysis also demonstrated differences in gender for other immune checkpoints (e.g., LAG3 and IDO1) used in clinical trials 37,38 , suggesting the future consideration of gender effects in ICB trials. Interestingly, we observed discrepant pattern between the mRNA expression and protein expression of PD-L1, which may due to the moderate correlation of mRNA and protein ( Supplementary Fig.…”

Single-cell analysis reveals new evolutionary complexity in uveal melanoma

“…LAG3 is the third immunoinhibitory receptor to be targeted in patients, demonstrates considerable synergy with PD1, is expressed not only on CD8 + T cells but also on NK cells and regulatory T cells, and has unique properties that could significantly expand the efficacy of checkpoint inhibitor therapy 18 . As such, LAG3 inhibitors are being evaluated in a large number of clinical trials in multiple cancer types 23 .…”

Loading of Primary Human T Lymphocytes with Citrate-Coated Superparamagnetic Iron Oxide Nanoparticles Does Not Impair Their Activation after Polyclonal Stimulation

“…In addition to analyzing the influence of loading the T cells with SPION Citrate on the release of IL-2, the expression of different activation markers was also investigated. Cell surface staining for the activation markers CD25 and CD69 as well as the checkpoint molecules programmed cell death 1 (PD-1, CD279), lymphocyte activation gene 3 (LAG-3, CD223), and T cell immunoglobulin and mucin domain containing 3 (Tim-3, CD366) were analyzed by flow cytometry [56][57][58][59][60][61][62][63][64]. After exclusion of doublets and higher cell aggregates, dead cells were excluded by DAPI staining and only DAPI − cells were evaluated [65].…”