Background: The protumor activities of cancer-associated fibroblasts (CAFs) suggest that they are potential therapeutic targets for the treatment of cancer. The mechanism of CAF heterogeneity in gastric cancer (GC) remains unclear and has slowed translational advances in targeting CAFs. Therefore, a comprehensive understanding of the classification, function, activation stage, and spatial distribution of the CAF subsets in GC is urgently needed.

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, but its clinical benefit is limited in advanced gastric cancer (GC). Cancer-associated fibroblasts (CAFs) have been reported to be associated with ICB resistance, but the underlying mechanism has not been fully elucidated. Our previous single-cell RNA-seq analysis of GC revealed that POSTN+FAP+ extracellular matrix CAFs (eCAFs) communicate with macrophages. Here, we evaluated the correlation between eCAFs and ICB response in TCGA-STAD and real-world cohorts. Immune infiltration analysis and correlation analysis were performed to assess the relationship between eCAFs and macrophages. We first confirmed a negative correlation between the abundance of eCAFs and the overall response rate (ORR) to anti-PD-1 treatment in TCGA-STAD and real-world GC cohorts. Overexpression of POSTN in CAFs enhanced macrophage chemotaxis, while POSTN interference showed the opposite effect in vitro and in vivo. Furthermore, the cell density of POSTN+ CAFs was positively correlated with the infiltration level of CD163+ macrophages in GC patient tissues. The results demonstrated that POSTN secreted by CAFs enhances macrophage chemotaxis by activating the Akt signaling pathway in macrophages. Additionally, we found that POSTN+FAP+ eCAFs may exist in multiple solid tumors and are associated with ICB resistance. eCAFs promote macrophage chemotaxis through the secretion of POSTN, thereby leading to ICB resistance. High expression of POSTN is likely to predict a poor response to ICB. POSTN downregulation may be considered as a candidate therapeutic strategy to improve ICB efficacy.

Background: Organ-specific response patterns reported in previous studies indicate different response toward immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) patients with different metastatic sites. This study aims to compare the efficacy of ICIs with conventional therapy in NSCLC patients with bone, brain or liver metastases. Materials and Methods: MEDLINE, Embase, and CENTRAL were searched for studies comparing ICIs with conventional therapy in NSCLC patients with bone, brain or liver metastases. The pooled hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS) among included studies was analyzed using the random effects model. Results: Eight studies consisting of 988 NSCLC patients were included, 259 with brain metastases and 729 with liver metastases. No available study with bone metastases information was identified. For patients with brain metastases, ICIs significantly improved their OS (HR, 0.57; P = 0.007). For patients with liver metastases, both OS (HR, 0.72; P = 0.006), and PFS (HR, 0.72; P = 0.004) improvements were observed in the ICI treatment arm. Subgroup analysis was conducted based on target of ICIs and treatment regimen. PD-1 inhibitors could benefit patients with liver or brain metastases on OS and PFS (brain metastases: OS, HR, 0.43; P < 0.001; liver metastases: PFS, HR, 0.52; P = 0.003; OS, HR, 0.66; P = 0.001), while PD-L1 inhibitors could not. Patients with brain metastases could only gain OS improvement from ICIs combined with chemotherapy (HR, 0.41; P = 0.001), but for patients with liver metastases, the benefit was detected using ICIs single agent (HR, 0.68; P = 0.012) or ICIs combined with chemotherapy plus anti-VEGF therapy (HR, 0.52; P = 0.005). Conclusion: ICIs could significantly improve OS in NSCLC patients with brain or liver metastases compared with conventional therapy. Patients with brain metastases could only gain OS benefit from ICIs combined with chemotherapy, while those with liver metastases obtained superior OS from ICIs single agent or ICIs combined with chemotherapy plus anti-VEGF therapy.

Background: Treatment strategies are limited for patients with chemotherapy refractory microsatellite stable (MSS) colorectal cancer. We aim to evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) combined with regorafenib in this population in routine clinical practice. Methods: We retrospectively analyzed patients with advanced or metastatic colorectal cancer who received at least one dose of ICIs combined with regorafenib in 14 Chinese medical centers. The primary outcome was objective response rate (ORR). This study was registered at ClinicalTrials.gov on February 2020 (NCT04771715). Results: Eighty-four patients received ICIs combined with regorafenib from January 2019 to January 2021. Most patients (91%) received two or more systemic treatment lines before the study treatment. Seventy-six patients (90%) had confirmed MSS status. At a median follow-up of 5.5 months, four patients achieved partial response (5%) and 37 patients achieved stable disease (45%) as the best response. The median progression-free survival (PFS) was 3.1 months, and the median overall survival was 17.3 months. Eleven patients (13%) remained progression-free for more than 6 months. Baseline liver metastasis (HR 1.98, 95%CI 1.07–3.69, P = 0.03) and neutrophil–lymphocyte ratio (NLR) of ≥ 1.5 (HR 2.83, 95%CI 1.00–7.98, P = 0.05) were associated with shorter PFS in multivariate analysis. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 16 patients (19%). Conclusion: The combination of ICIs with regorafenib can be a valuable treatment option for a proportion of patients with chemotherapy refractory MSS colorectal cancer. Patients with no liver metastasis and a low NLR at baseline may derive most benefit from this strategy.

Alpha-fetoprotein-producing gastric cancer (AFPGC) poses a therapeutic challenge worldwide because of its poor prognosis. This study aimed to evaluate the efficacy and safety of antiangiogenic drug apatinib in advanced AFPGC in a real-world setting. From September 2015 to December 2017, twenty-one patients identified with AFPGC from the clinical trial AHEAD-G202, an open-label, prospective, multicenter, non-interventional study of apatinib for advanced metastatic gastric cancer, were enrolled to perform this analysis. Patients received oral apatinib as monotherapy or combination therapy. A treatment cycle was defined as 28 days. The primary outcome was progression-free survival (PFS) and overall survival (OS), and the secondary outcomes included safety, objective response rate (ORR), and disease control rate (DCR). Twenty patients were evaluated for the apatinib efficacy analysis. The ORR of apatinib was 10%, whereas the DCR was 70%. The median PFS was 3.5 months [95%confidence interval (CI): 2.34-4.66]. The median OS was 4.5 months (95%CI: 3.49-5.51). Median OS of AFPGC patients without carcinoembryonic antigen (CEA) elevation achieved 30.8 months. CEA elevation was considered to be a potential independent predictive factor for OS (P = 0.030) and PFS (P = 0.047) by the analysis of multivariate analysis. The most common grade 3 to 4 adverse events (AEs) were hypertension (4.8%), hand-foot syndrome (4.8%), anorexia (4.8%), and vomiting and nausea (4.8%). Apatinib showed promising efficacy and an acceptable safety profile in patients with advanced AFPGC. Antiangiogenic therapy may be a good strategy for the treatment of AFPGC as a rare sub-type of gastric cancer. AHEAD-G202 (NCT02668380).