Current anti-angiogenic therapies have changed the paradigm of treating colorectal cancer (CRC) patients with advanced diseases. However, the clinical response rate is still low at less than 10% due largely to complex angiogenic factors released by tumor cells. Exploring novel mechanisms of tumor angiogenesis and identifying alternative targets for combination therapies are therefore essential to effective inhibition of tumor vascularization and CRC development. Immunoglobulin-like transcript 4 (ILT4), initially identified as a suppressor of myeloid cell activity, is enriched in solid tumor cells. ILT4 favors tumor progression by inducing tumor malignant biologies as well as an immunosuppressive microenvironment. However, whether and how tumor-derived ILT4 orchestrates tumor angiogenesis is still undetermined. Here we found that tumor-derived ILT4 was positively correlated with microvessel density in CRC tissues. ILT4 induced the migration and tube formation of HUVECs in vitro and angiogenesis in vivo. Mechanistically, the activation of MAPK/ERK signaling and subsequent up-regulation of vascular endothelial growth factor-A (VEGF-A) and fibroblast growth factor 1 (FGF-1) were responsible for ILT4-induced angiogenesis and tumor progression. Importantly, ILT4 inhibition suppressed tumor angiogenesis and enhanced the efficacy of Bevacizumab treatment in CRC. Our study has identified a novel mechanism for ILT4-mediated tumor progression, which signals a new therapeutic target and alternative combination strategies to combat CRC.
e20574 Background: For metastatic lung adenocarcinoma with low PD-L1 expression (tumor proportion score:1-49%), chemotherapy in combination with immune checkpoint inhibitors (IC), with bevacizumab (BC), or with both (IBC) have been established as standard first-line options. However, the optimal scheme is still undetermined. Methods: This retrospective study enrolled 125 metastatic lung adenocarcinoma patients with low PD-L1 expression from four cancer centers. All the patients received IC, BC, or IBC as the first-line therapies. Propensity score matching (PSM) with a ratio of 1:1:1 was used to balance the inter-group clinical characteristics. Efficacy, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS), as well as safety were evaluated. Results: 35 of the 125 patients received IBC, 37 received BC, and 53 received IC. After PSM, a total of 35 pairs of patients were enrolled in the analysis. Patients receiving IBC (ORR: 57.1%, DCR:100%) or IC (ORR: 57.1%, DCR: 91.4%) obtained superior ORR and DCR in relative to those receiving BC (ORR: 45.7%, DCR: 82.9%). However, only IBC (median PFS: 20.47m; median OS: not research) rather than IC (median PFS: 10.0m; median OS: 21.36m) treatment generated significantly prolonged PFS and OS compared with BC (median PFS: 9.43m, P = 0.007; median OS: 23.2m, P = 0.048). We further analyzed the survival benefit based on different clinical and molecular features. We found patients with female gender had more significant OS benefit from IBC treatment over IC or BC treatment. In addition, non-smokers benefit more from IBC compared with IC. The occurrence of adverse events (AEs) was more frequent in IBC (74.3%) and IC (85.7%) group in relative to BC group (42.8%). Meanwhile, ≥ grade 3 AEs (22.9%) was markedly higher in IBC group compared with that in BC group (5.7%). However, leukopenia and neutropenia represent the most common ≥ grade 3 AEs, which are easy to be clinically managed. Conclusions: For metastatic lung adenocarcinoma patients with low PD-L1 expression, IBC is the preferred first-line therapy in terms of survival. However, the AEs should be carefully concerned.
e14647 Background: The low response of immune checkpoint inhibitors against PD-1/PD-L1 in cancer patients calls for further development of new immune targets. Immunoglobulin-like transcript (ILT)3 and its ligand ApoE have been demonstrated to be highly expressed in a variety of malignant tumor cells and involved in tumor biological behaviors, including invasion and angiogenesis. ILT3 targeting drugs are undergoing increasing preclinical and clinical trials. However, the role of tumor-derived ILT3 in immune regulation is unclear. The aim of this study was to investigate the immunomodulatory effect of tumor-derived ILT3 and its immunotherapy therapeutic efficacy that combination with PD-L1 blockade in NSCLC. Methods: The correlations between ILT3/ApoE expression and prognosis of NSCLC patients were analyzed basing on public databases. Multiplex immunofluorescence was performed to analyze the correlations between tumor-derived ILT3/ApoE expression and intratumoral immune cells infiltration in human adenocarcinoma tissues. The impact of ILT3 and ApoE on tumor-associated macrophage (TAM) recruitment and polarization were evaluated by transwell migration assay, flow cytometry, and RT-PCR, while their direct impact on T cell survival and cytotoxicity was detected by flow cytometry. Using lung cancer xenograft murine models, we further confirmed the pro-tumoural activity of tumor-derived gp49B and analyzed its correlations with immune cells in vivo. Tumor immunotherapy models targeting at gp49B and/or PD-L1 were established in C57BL/6 mice inoculated with LLC cells. Gp49b inhibition was implemented by infection of specific knockdown lentivirus and PD-L1 was blocked using mouse neutralizing antibodies. Flow cytometry was performed to detect the frequency and phenotype of macrophages and T cells in the tumors, spleen, and blood of the mice. Results: Patients with high expression of ILT3 had significantly worse prognosis in LUAD, but not in LUSC. In vitro assays demonstrated that tumor-derived ILT3/ApoE promoted recruitment and M2-like polarization of TAMs and directly inhibited the proliferation and cytotoxicity of T cells, which had been further confirmed in vivo models. Moreover, ILT3 (gp49B) inhibition enhanced anti-tumor immunity and suppressed tumor progression by counteracting TAM- and dysfunctional T cell- induced immunosuppressive TME; the combined inhibition of gp49B and PD-L1 showed the most dramatic tumor retraction in LLC xenograft models. Conclusions: Tumor-derived ILT3 overexpression suppressed anti-tumor immunity by recruiting M2-like TAMs and directly impairing T cell activities, while ILT3 inhibition counteracted above immunosuppression and potentiated the efficacy of PD-L1 blockade in LUAD. Our study verified that ILT3 may be a promising novel immunotherapeutic target for LUAD patients.
Abstract Antiangiogenic therapy targeting VEGF‐A has become the standard of first‐line therapy for non‐small cell lung cancer (NSCLC). However, its clinical response rate is still less than 50%, and most patients eventually develop resistance, even when using combination therapy with chemotherapy. The major cause of resistance is the activation of complex bypass signals that induce angiogenesis and tumor progression. Therefore, exploring novel proangiogenic mechanisms and developing promising targets for combination therapy are crucial for improving the efficacy of antiangiogenic therapy. Immunoglobulin‐like transcript (ILT) 4 is a classic immunosuppressive molecule that inhibits myeloid cell activation. Recent studies have shown that tumor cell‐derived ILT4 drives tumor progression via the induction of malignant biologies and creation of an immunosuppressive microenvironment. However, whether and how ILT4 participates in NSCLC angiogenesis remain elusive. Herein, we found that enriched ILT4 in NSCLC is positively correlated with high microvessel density, advanced disease, and poor overall survival. Tumor cell‐derived ILT4 induced angiogenesis both in vitro and in vivo and tumor progression and metastasis in vivo. Mechanistically, ILT4 was upregulated by its ligand angiopoietin‐like protein 2 (ANGPTL2). Their interaction subsequently activated the ERK1/2 signaling pathway to increase the secretion of the proangiogenic factors VEGF‐A and MMP‐9, which are responsible for NSCLC angiogenesis. Our study explored a novel mechanism for ILT4‐induced tumor progression and provided a potential target for antiangiogenic therapy in NSCLC.
e20560 Background: Immunochemotherapy combinations have been the mainstream first-line standard treatment of advanced non-small cell lung cancer (NSCLC), wherein concurrent chemotherapy and immunotherapy are conventionally fixed to an established dosing regimen. Few studies had suggested the remarkable impact of the timing of immunotherapy on immunochemotherapy combined therapy. However, this issue has not been addressed in advanced NSCLC cohort. Methods: This study was a retrospective analysis of 532 patients with advanced lung adenocarcinoma (LUAD) without EGFR/ALK mutations who underwent immunochemotherapy as first-line systemic treatment between June 2018 to June 2022 at 3 facilities. Patients were divided into two groups (induced and non-induced) according to the different timing of immunotherapy in combined therapy, which defined induced as receiving 1 or more cycles of full-dose chemotherapy alone before concurrent immunochemotherapy. The bias between induced and non-induced groups was minimized with Propensity Score Matching (PSM). Patients outcomes, including progression-free survival (PFS) and overall survival (OS), were compared between the two groups by Kaplan-Meier survival curves and Cox regression analyses. Results: Survival analysis showed that both PFS and OS of the induced chemotherapy group patients were significantly longer than that of non-induced group (PFS: 14.63 months vs. 10.13 months, p = 0.004; OS: Not reached vs. 20.27 months, p = 0.0013). In the COX regression, after adjusting for confounders, induction chemotherapy was found to be a remarkable favorable factor for both PFS and OS (PFS: HR = 0.73, p= 0.018; OS: HR = 0.69, p= 0.034). After pretreatment features and treatment parameters were included in PSM, 104 patients were identified in each groups with matched characteristics, and moreover, the results of survival analysis remained consistent and showed significant difference between induced and non-induced group (PFS: 14.63 months vs. 10.23 months, p = 0.029; HR = 0.71, p= 0.030. OS: Not reached vs 18.27 months, p = 0.0013; HR = 0.52, p= 0.002). Conclusions: For advanced LUAD patients treated with first-line immunochemotherapy combinations, the timing of immunotherapy had significant impact on prognosis, which suggested notable benefit of induction chemotherapy before concurrent immunochemotherapy.
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