BackgroundMonoclonal antibodies of anti-epidermal growth factor receptor (EGFR) have been recommended as first-line therapy for patients with left-sided metastatic colorectal cancer (mCRC) with wild-type RAS. The effect of tumour laterality on antivascular endothelial growth factor antibody and how to optimise targeted therapies for the right-sided cases remain controversial.Patients and methodsA comprehensive meta-analysis enrolling 16 first-line clinical trials was performed to evaluate the efficacy of chemotherapy alone and chemotherapy plus targeted therapies for patients with mCRC with right primary tumour site, and we validated the results in metastatic setting (14 trials containing 4306 patients with unresectable mCRC).ResultsHere, we found that progression-free survival (PFS) (combined HR 1.30, 95% CI 1.17 to 1.44) and overall survival (OS) (combined HR 1.46, 95% CI 1.32 to 1.62) of the right-sided patients were significantly inferior to the left-sided individuals receiving chemotherapy alone in overall population, regardless of race. Similar results were also observed in metastatic setting. OS of patients with left-sided mCRC receiving chemotherapy plus bevacizumab was superior to the right-sided individuals (combined median survival ratio (MSR)=1.23, 95% CI 1.08 to 1.39 for overall population; combined MSR=1.23, 95% CI 1.05 to 1.45 for metastatic setting), especially for wild-type RAS and mixed population. Moreover, the right-sided patients benefited more from chemotherapy plus bevacizumab comparing with chemotherapy alone in both overall population and metastatic setting. Importantly, the RAS-wild right-sided patients achieved longer PFS (combined HR 0.67, 95% CI 0.52 to 0.88) and OS (combined HR 0.74, 95% CI 0.56 to 0.98) from chemotherapy plus bevacizumab comparing with chemotherapy associated with anti-EGFR agents.ConclusionsPatients with right-sided mCRC show impaired chemosensitivity, and chemotherapy plus bevacizumab can be an optimal first-line therapeutic regimen for the RAS-wild patients with right-sided mCRC.

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The emerging debate between primary tumor location and clinical outcome of bevacizumab treated metastatic colorectal cancer (mCRC) continues. The aim of the present study is to investigate the association between the primary tumor location and clinical outcome of 115 mCRC patients receiving bevacizumab based treatment. A meta-analysis including 21 studies was carried out to confirm the conclusion. In our prospective study, we found that right-sided mCRC commonly occurred in older cases ( p = 0.03) with multiple-site metastasis ( p = 0.03). Progression-free survival (PFS) of the left-sided patients undergoing bevacizumab plus a FOLFIRI regimen was superior to the right-sided cases ( p = 0.03, crude HR = 0.31, 95%CI = 0.11–0.87; adjusted HR = 0.21, 95%CI = 0.06–0.66). The meta-analysis confirmed that efficacy of bevacizumab-based treatment in left-sided mCRC patients was better than the right-sided cases in the overall population ( P h = 0.24, combined OR = 1.36, 95%CI = 1.07–1.72), RAS / BRAF wild-type ( P h = 0.19, combined OR = 1.66, 95%CI = 1.17–2.34), clinical trial ( P h = 0.23, combined OR = 1.42, 95%CI = 1.07–1.88), Caucasian population ( P h = 0.18, combined OR = 1.37, 95%CI = 1.02–1.85) and first-line ( P h = 0.19, combined OR = 1.48, 95%CI = 1.13–1.96) subgroups. Improved survival of bevacizumab plus chemotherapy treated left-sided mCRC patients was observed in the overall population [ P h < 0.01, combined MSR = 1.09, 95%CI = 1.00–1.18 for PFS; P h < 0.01, combined MSR = 1.24, 95%CI = 1.13–1.36 for overall survival (OS)], especially in the RAS/BRAF wild-type ( P h = 0.09, combined MSR = 1.10, 95%CI = 1.03–1.19 for PFS; P h = 0.02, combined MSR = 1.34, 95%CI = 1.21–1.49 for OS). These findings indicate that primary tumor sidedness can predict clinical outcome of bevacizumab-treated RAS/BRAF wild-type mCRC patients and the left-sided patients may benefit more from bevacizumab plus FOLFIRI.

Macrophage phagocytosis plays essential roles in antitumor immunity. CD47/SIRPα phagocytosis checkpoint blockade has demonstrated therapeutic potential in several hematopoietic cancers, but recent clinical studies reported very limited efficacy against solid malignancies. Here, we show that polyinosinic‐polycytidylic acid (Poly(I:C)), a synthetic analog of double‐stranded RNA, enhances the antitumor activity of CD47 blockade in colorectal cancer in vitro and in vivo. Poly(I:C) activation leads to a potent immune response characterized by the production of proinflammatory cytokines, especially IL‐6. Stimulation with IL‐6 promotes the PI3K signaling and cytoskeletal reorganization required for macrophage phagocytosis mediated by CD47 blockade. Our findings demonstrate the potential of Poly(I:C) to synergize the efficacy of CD47 blockade therapy and a novel role for IL‐6 in macrophage phagocytosis, which provide new strategy for combinational cancer immunotherapy.

Background: Globally, colorectal cancer (CRC) is one of the most lethal malignant diseases. However, the currently approved therapeutic options for CRC failed to acquire satisfactory treatment efficacy. Tailoring therapeutic strategies for CRC individuals can provide new insights into personalized prediction approaches and thus maximize clinical benefits. Methods: In this study, a multi-step process was used to construct an immune-related genes (IRGs) based signature leveraging the expression profiles and clinical characteristics of CRC from the Gene Expression Omnibus (GEO) database and the Cancer Genome Atlas (TCGA) database. An integrated immunogenomic analysis was performed to determine the association between IRGs with prognostic significance and cancer genotypes in the tumor immune microenvironment (TIME). Moreover, we performed a comprehensive in silico therapeutics screening to identify agents with subclass-specific efficacy. Results: The established signature was shown to be a promising biomarker for evaluating clinical outcomes in CRC. The immune risk score as calculated by this classifier was significantly correlated with over-riding malignant phenotypes and immunophenotypes. Further analyses demonstrated that CRCs with low immune risk scores achieved better therapeutic benefits from immunotherapy, while AZD4547, Cytochalasin B and S-crizotinib might have potential therapeutic implications in the immune risk score-high CRCs. Conclusions: Overall, this IRGs-based signature not only afforded a useful tool for determining the prognosis and evaluating the TIME features of CRCs, but also shed new light on tailoring CRCs with precise treatment.