The immunologic advantage of recurrent nasopharyngeal carcinoma from the viewpoint of Galectin-9/Tim-3-related changes in the tumour microenvironment

Abstract

Given salvage treatment for recurrent nasopharyngeal carcinoma (NPC) remains a clinical dilemma, immunotherapy targeting NPC-specific immunosuppression may bring new hope. We analyzed the expression of CD8, CD4, Foxp3 and Tim-3 in lymphocytes, and of Galectin-9 in tumour cells between paired primary and recurrent NPC from 95 patients and we noted that there was significant increase in the expression of Galectin-9+ tumour cells (p < 0.001) and Foxp3+ lymphocytes (p < 0.001) but a significant decrease in the expression of CD8+ lymphocytes (p = 0.01) between paired primary and recurrent NPC. Of all patients, 53 patients (55.79%) and 57 patients (60%) had increased percentages of Galectin-9+ tumour cells and of Foxp3+ lymphocytes, respectively. Conversely, 42 patients (44.21%) had decreased percentages of CD8+ lymphocytes. The patients with high Galectin-9 expression in recurrent NPC frequently also had high Tim-3 (p = 0.04) and Foxp3 (p = 0.01), and low CD8 (p = 0.04) expression in lymphocytes. After multivariate analyses, low CD8 expression in lymphocytes was an independent risk factor for relapse-free survival (p = 0.002) and overall survival (p = 0.02). Our data suggests that recurrent NPC may had more immunologic advantage than primary NPC, especially the Galectin-9/Tim-3 pathway. The immunotherapies targeting Galectin-9/Tim-3/Foxp3 interaction may serve as a potential salvage treatment for recurrent NPC.

TIM-3 expression in breast cancer

“…TIM-3 immunohistochemistry was conducted with anti-TIM-3 rabbit monoclonal antibody clone D5D5R from Cell Signaling (Cat# 45208) as employed in other publications 21,33,49,50 , here using a Ventana Ultra automated stainer (Ventana Medical Systems) in concordance with manufacturer’s protocol. In brief, slides underwent antigen retrieval with Standard Cell Conditioning 1 reagent (Ventana Medical Systems) followed by 60 minutes of primary antibody incubation (applied at 1:50 dilution) with no heat, and visualized using a chromoMap DAB detection kit (Ventana Medical Systems).…”

Role of Galectins in Tumors and in Clinical Immunotherapy

“…The role of galectin-9 in the regulation of the immune response in the tumor microenvironment has been investigated further in patients with recurrent nasopharyngeal carcinoma. Such patients displayed increased galectin-9-positive tumor cells and FOXP3 + lymphocytes, whereas the TIM-3 + lymphocytes were decreased in the tumor microenvironment compared with primary NPCs, suggesting that the galectin-9–TIM-3 pathway mediates immune escape by NPCs [ 46 ]. This pathway also downregulates the antitumor response in hepatitis B virus-associated HCCs.…”

Association of Serum T cell Immunoglobulin Domain and Mucin-3 and Interleukin-17 with Systemic Lupus Erythematosus

“…Administration of antibodies against Tim-3 can significantly exacerbate the clinical and pathologic severity of EAE and can increase the number and activation level of macrophages [ 21 , 47 ]. The Tim-3/Galectin-9 pathway has been well established, and such signaling can lead to the apoptosis of effector CD4+ and CD8+ T cells [ 48 ]. This suggests that the Tim-3/Galectin-9 pathway is an immunosuppressive pathway in response to Th1 and Th17-mediated inflammation.…”