Lymphocyte-activation gene 3 (LAG3): The next immune checkpoint receptor

Abstract

Immune checkpoint therapy has revolutionized cancer treatment by blocking inhibitory pathways in T cells that limits the an effective anti-tumor immune response. Therapeutics targeting CTLA-4 and PD1/PDL1 have progressed to first line therapy in multiple tumor types with some patients exhibiting tumor regression or remission. However, the majority of patients do not benefit from checkpoint therapy emphasizing the need for alternative therapeutic options. Lymphocyte Activation Gene 3 (LAG3) or CD223 is expressed on multiple cell types including CD4 + and CD8 + T cells, and T regs , and is required for optimal T cell regulation and homeostasis. Persistent antigen-stimulation in cancer or chronic infection leads to chronic LAG3 expression, promoting T cell exhaustion. Targeting LAG3 along with PD1 facilitates T cell reinvigoration. A substantial amount of pre-clinical data and mechanistic analysis has led to LAG3 being the third checkpoint to be targeted in the clinic with nearly a dozen therapeutics under investigation. In this review, we will discuss the structure, function and role of LAG3 in murine and human models of disease, including autoimmune and inflammatory diseases, chronic viral and parasitic infections, and cancer, emphasizing new advances in the development of LAG3-targeting immunotherapies for cancer that are currently in clinical trials.

CTLA4 has a profound impact on the landscape of tumor-infiltrating lymphocytes with a high prognosis value in clear cell renal cell carcinoma (ccRCC)

“…Activation of the PD-1/PD-L1 signaling pathway contributes to TME with immune evasion, and its inhibitors are representative, which have been used in lots of solid tumors (41). LAG3 can negatively regulate the activation and function of T cells, and its antagonists have been applied clinically (42). At present, some studies have been devoted to the synergism between LAG3 and PD-1 in enhancing the e cacy of immunotherapy (43).…”

CTLA4 had a profound impact in the landscape of tumor-infiltrating lymphocytes with a high prognosis value in ccRCC

“…Activation of the PD-1/PD-L1 signaling pathway contributes to TME with immune evasion, and its inhibitors are representation, which have been used in lots of solid tumors (35). LAG3 can negatively regulate the activation and function of T cells, and its antagonists have been applied clinically (36). At present, some studies have been devoted to the synergism between LAG3 and PD-1 in enhancing the e cacy of immunotherapy (37).…”

Trial watch: IDO inhibitors in cancer therapy

“…[192][193][194] BMS-986205 is mainly being administered to cancer patients simultaneously receiving nivolumab 195 (NCT03792750, NCT03459222, NCT03519256, NCT03661320, NCT04106414, NCT04047706, NCT03695250, NCT03854032, NCT04007588, NCT03417037). Patients affected by advanced solid tumors are treated with BMS-986205 plus nivolumab alone (NCT03792750) or combined with the anti-lymphocyte activating 3 (LAG3) agent relatlimab 54,[196][197][198][199]. The Phase II study NCT03519256, enrolling subjects with high-risk, non-MIBC, is monitoring the therapeutic profile of BMS-986205 combined with two drugs already approved for some types of bladder cancer such as nivolumab [200][201][202][203][204] and the toll like receptor 2 (TLR2)/TLR4 agonist [205][206][207][208][209] bacillus Calmette-Guérin (BCG).…”