Assessment of the expression and response of PD-1, LAG-3, and TIM-3 after neoadjuvant radiotherapy in rectal cancer

Abstract

Many studies have verified the safety of combined radiotherapy and immune checkpoint blockades iation dose or sequencing of combination. We aimed to evaluate the expression and response of PD-1, TIM-3, LAG-3 after neoadjuvant radiotherapy (NRT) and explore the possibility and optimal schedule of combining immunotherapy with radiotherapy in treating rectal cancer. Immunohistochemistry was performed to detect the expression of PD-1, TIM-3, LAG-3, CD8, and CD3. These molecules' expression was detected on the specimens of 76 rectal cancer patients following NRT and 13 of these patients before NRT. The expression of ICBs was assessed by the percentage of positive cells. The levels of PD-1 and immune cells (ICs) LAG-3 in rectal cancer increased after NRT (0% vs. 3%, P = 0.043 and 5% vs. 45%, P = 0.039, respectively). However, TIM-3 in ICs and tumor cells (TCs) were both decreased (80% vs. 50%, P = 0.011, 90% vs. 0%, P = 0.000, respectively). The LAG-3 expression was higher in patients treated with short-course RT than longcourse RT (22.5% vs. 8.0%, P = 0.0440 in ICs; 0% vs. 70%, P < 0.001 in TCs). On the co ntrary, CD8 was higher after long-course RT (15% vs. 8%, P = 0.0146). Interestingly, the level of ICs TIM-3 was low in > eight weeks after long-course RT (P = 0.045). The expressions of PD-1, ICs TIM-3, ICs LAG-3, CD3, and CD8 were associated with the disease-free survival (DFS) in univariate analysis (P = 0.036, 0.008, 0.018, 0.025, and 0.004, respectively). Adjusted by the relevant variables, PD-1 (HR 0.274; 95%

Immune Checkpoint LAG3 and Its Ligand FGL1 in Cancer

“…Peng et al found that the expression of LAG3 after neoadjuvant radiotherapy (NRT) significantly increased in rectal cancer, especially for short-term NRT, and that this high expression may induce a better treatment effect. Thus, it is reasonable to consider that the combination of NRT with immunotherapy may be an alternative for patients with advanced rectal cancer (76).…”

Prognostic significance of Lymphocyte-activation gene 3 (LAG3) in patients with solid tumors: a systematic review, meta-analysis and pan-cancer analysis

“…Two studies each explored the survival outcome of patients with BLCA [ 36 , 63 ], COAD [ 39 , 49 ], LIHC [ 34 , 42 ], THCA [ 44 , 53 ], STAD [ 45 , 47 ], and SKCM [ 38 , 40 ]. Only one study each reported the survival outcome of non-small cell lung cancer (NSCLC) [ 35 ], CESC [ 66 ], KIRC [ 33 ], SARC [ 41 ], READ [ 48 ], COADREAD [ 58 ], PAAD [ 52 ], and UCEC [ 65 ]. Thirty-two of the included studies reported the correlation between LAG3 expression and OS [ 24 – 35 , 37 , 38 , 40 , 42 , 44 – 47 , 50 , 51 , 54 – 59 , 62 – 64 , 66 ], fourteen reported the correlation LAG3 expression and DFS [ 24 – 26 , 33 , 34 , 39 , 42 , 43 , 45 , 46 , 48 , 49 , 52 , 60 ], ten reported the correlation between LAG3 expression and PFS [ 37 , 38 , 41 , 47 , 50 , 61 – 64 , 66 ], and eight reported the correlation between LAG3 expression and RFS [ 27 , 31 , 35 , 36 , 53 ...…”

“…Fourteen studies involving 2,026 patients investigated the correlation between the expression of LAG3 and DFS [ 24 – 26 , 33 , 34 , 39 , 42 , 43 , 45 , 46 , 48 , 49 , 52 , 60 ]. The pooled analysis showed that there was no significant correlation between LAG3 expression and DFS (HR = 1.41, 95% CI 0.96–2.07, P = 0.078), as shown in Fig.…”

Immune Response and Immune Checkpoint Molecules in Patients with Rectal Cancer Undergoing Neoadjuvant Chemoradiotherapy: A Review

“…The role of LAG-3 and TIM-3 has not been extensively studied in rectal cancer (Tables 2 and 3). Peng et al investigated the expression of LAG-3 and TIM-3 in 76 rectal cancer patients treated with preoperative RT [106]. LAG-3-expressing immune cells increased in cancer tissues after RT, while TIM-3 decreased.…”