LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma

Abstract

Immunotherapy with immune checkpoint molecule-specific monoclonal antibody have obtained encouraging results from preclinical studies and clinical trials, which promoted us to explore whether this kind of immunotherapy could be applicable to head and neck squamous cell carcinoma (HNSCC). Lymphocyte activation gene-3 (LAG-3) is an immune checkpoint control protein that negatively regulates T cells and immune response. Here, using the human tissue samples, we report these findings that LAG-3 is overexpressed on tumorinfiltrating lymphocytes (TILs; p < 0.001) and its overexpression correlates with the high pathological grades, lager tumor size and positive lymph node status in human primary HNSCC. Survival analysis identifies LAG-3 as a prognostic factor independent of tumor size and pathological grades for primary HNSCC patients with negative lymph node status (p D 0.014). Study in immunocompetent genetically defined HNSCC mouse model reports that LAG-3 is upregulated on CD4 C T cells, CD8 C T cells and CD4 C Foxp3 C regulatory T cells (Tregs). In vivo study, administration of LAG-3-specific antibody retards tumor growth in a way associated with enhanced systemic antitumor response by potentiating the antitumor response of CD8 C T cells and decreasing the population of immunosuppressive cells. Taken together, our results offer a preclinical proof supporting the immunomodulatory effects of LAG-3 and suggest a potential therapeutic target of immunotherapy for HNSCC.

Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using Multiplex Quantitative Analysis

“…Moreover, we found high levels of LAG-3 + cells were independent predictor of poor OS and DFS. Similar to our result, high expression of LAG-3 predicted poor survival in head and neck squamous cell carcinoma [41], melanoma [37], soft tissue sarcomas [42] and nonsmall cell lung cancer(NSCLC) [40]. On the contrary, other studies in esophageal squamous cell carcinoma [43], breast cancers [39] and NSCLC [44]show the opposite results, and only one study in HCC has showed no prognostic significance [45].…”

Co‐inhibitory immune checkpoints in head and neck squamous cell carcinoma

“…Previous reports demonstrated that LAG‐3 was highly expressed on the surface of CD4 + CD25 high Foxp3 + Tregs in HNSCC and LAG‐3 blockade relieved the inhibitory function of Tregs (Jie et al., ). Consistent with these reports, another study found that LAG‐3 was upregulated on Tregs and inhibition of LAG3 decreased the population of immunosuppressive cells in HNSCC mouse models (Deng et al., ). The anti‐LAG3 blocking mAb, BMS‐986016, alone or in combination with nivolumab, has entered to phase I trial (NCT01968109) for solid tumors, including HNSCC.…”

“…LAG‐3 (CD223), which is expressed on activated CD4 + and CD8 + T cells, NK cells, B cells, and plasmacytoid dendritic cells, is a co‐inhibitory immune checkpoint molecule (Deng et al., ). Although the known LAG‐3 ligand is the MHC II molecule, recent studies suggested that LSECtin molecule, which expressed in many tumors, may be another LAG‐3 ligand (Xu et al., ).…”

Altered expression of TIM‐3, LAG‐3, IDO, PD‐L1, and CTLA‐4 during nimotuzumab therapy correlates with responses and prognosis of oral squamous cell carcinoma patients

“…It was found that high checkpoint receptors expressed patients had a significantly shorter overall survival time in several malignancy . LAG‐3 and PD‐L1 have been confirmed as a prognostic factor independent of OSCC patients . TIM‐3 was reported to be upregulated in OSCC patients and associated with lymph node metastasis .…”

“…27 LAG-3 and PD-L1 have been confirmed as a prognostic factor independent of OSCC patients. 28 TIM-3 was reported to be upregulated in OSCC patients and associated with lymph node metastasis. 19 Increased expression of immunomodulator IDO was as- immunosuppressive microenvironment and combination therapy would be rational.…”