Tumor-associated macrophages (TAMs) have key functions in promoting a suppressive tumor immune microenvironment (TIME) and immune evasion, which largely limit treatment effects of immune checkpoint inhibitors (ICIs) in different cancers, including gastric cancer (GC). Dickkopf-1 (DKK1) associates with tumor progression and has been shown to negatively regulate anti-tumor immunity, but the impact of DKK1 on the TIME remains incompletely understood. Here, we found that tumoral DKK1 expression closely associated with worse survival and a suppressive TIME in GC patients. Results from in vitro co-culture assays suggested that DKK1 induces macrophages to become immunosuppressive, thereby inhibiting anti-tumor responses of CD8+ T cells and natural killer (NK) cells. In vivo DKK1 blockade in syngeneic GC mouse models reprogramed TAMs to restore the immune activity in the TIME and triggered significant tumor regression. DKK1 blockade also directly reduced growth of human GC tumors with high DKK1 expression in a xenograft model. Mechanistically, DKK1 interacted with cytoskeleton-associated protein 4 (CKAP4) on the macrophage surface and activated downstream PI3K-AKT signaling, which contributed to immune suppression. TAM reprogramming by DKK1 blockade also augmented the efficacy of programmed cell death protein-1 (PD-1) blockade in GC models. Therefore, our study provides novel insights into the role of DKK1 on tumor-intrinsic, innate, and adaptive anti-tumor immunity modulation and suggests that DKK1 is a promising immunotherapeutic target for enhanced PD-1 blockade therapy in GC.
Despite the successful application of chimeric antigen receptor (CAR)-T cell therapy in hematological malignancies, the treatment efficacy in solid tumors remains unsatisfactory, largely due to the highly immunosuppressive tumor microenvironment and low density of specific tumor antigens. Natural killer group 2 member D (NKG2D) CAR-T cells have shown promising treatment effects on several cancers such as lymphoma and multiple myeloma. However, the application and efficacy of NKG2D-CAR-T cells in gastric cancer (GC) still needs further exploration. This study identified a novel combination immunotherapy strategy with Dickkopf-1 (DKK1) inhibition and NKG2D-CAR-T cells, exerting synergistic and superior antitumor effect in GC. We show that the baseline expression of NKG2D ligands (NKG2DLs) is at low levels in GC tissues from The Cancer Genome Atlas and multiple GC cell lines including NCI-N87, MGC803, HGC27, MKN45, SGC7901, NUGC4, and AGS. In addition, DKK1 inhibition by WAY-262611 reverses the suppressive tumor immune microenvironment (TIME) and upregulates NKG2DL expression levels in both GC cell lines and GC tissues from a xenograft NCG mouse model. DKK1 inhibition in GC cells markedly improves the immune-activating and tumor-killing ability of NKG2D-CAR-T cells as shown by cytotoxicity assays in vitro. Moreover, the combination therapy of NKG2D-CAR-T and WAY-262611 triggers superior antitumor effects in vivo in a xenograft NCG mouse model. In sum, our study reveals the role of DKK1 in remodeling GC TIME and regulating the expression levels of NKG2DLs in GC. We also provide a promising treatment strategy of combining DKK1 inhibition with NKG2D-CAR-T cell therapy, which could bring new breakthroughs for GC immunotherapy.
e16098 Background: Systemic therapy options for patients with advanced gastric cancer (GC) are limited. We here presented the efficacy results for advanced GC patients matched to targeted therapies or immunotherapies based on the identification of tumor tissue genotypes. Methods: We selected 30 patients diagnosed between 2014 and 2020 with advanced GC at Nanjing Drum Tower Hospital, the affiliated Hospital of Nanjing University Medical School identified with actionable alterations and received ≥1 matched therapies. Tumor biopsy specimens from the patients were analyzed using NGS and/or selected immunohistochemistry and fluorescence in situ hybridization. Results: In these 30 patients, median age at diagnosis was 63 years (range 28-83) and 6 (20%) were female. In total, 11 (37%) harbored c-MET amplification/overexpression (received savolitinib or crizotinib, cohort A), 9 (30%) harbored HER2 mutation/overexpression (received RC48-ADC or trastuzumab, cohort B), 6 (20%) dMMR/MSI-H/TMB-H (received sintilimab, pembrolizumab, tislelizumab or nivolumab, combined with antivascular or not, cohort C), 2 (7%) KIT mutation/amplification (received imatinib or anlotinib, cohort D), 1 (3%) BRAF V600E mutation (received vemurafenib, cohort E) and 1 (3%) EGFR mutation (received afatinib, cohort F). Except for three patients in cohort C, all patients received at least one previous line systemic therapy. In cohort A, three of 11 patients had an objective response (1 complete response and 2 partial responses, objective response rate (ORR) 27%), disease control rate (DCR) was 45%, median progression-free survival (mPFS) was 2.1 months, and median overall survival (mOS) was 3.7 months. In cohort B, ORR was 44% (4/9), DCR was 78% (7/9), mPFS and mOS was 3.1 months and 5.5 months, respectively. In cohort C, ORR was 17% (1/6), DCR was 67% (4/6), mPFS and mOS was 1.9 months and 6.8 months, respectively. In cohort D, no patient had objective response or disease control. In cohort E, the one patient had PR. Stable disease was observed in the patient in cohort F. In all cohorts, ORR was 30% (9/30), DCR was 60% (18/30), mPFS and mOS was 2.7 months and 5.8 months, respectively. Conclusions: Overall, 30 patients with advanced GC were treated with matched therapies according to specific genotype. These real-world outcomes suggested that matched therapies for advanced GC has promising efficacy, supporting the adoption of genotyping in treatment determination.
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