Cancer Biology & Medicine最新文献

Objective: Neutrophils are one of the most predominant infiltrating leukocytes in lung cancer tissues and are associated with lung cancer progression. How neutrophils promote lung cancer progression, however, has not been established.

Methods: Kaplan-Meier plotter online analysis and tissue immunohistochemistry were used to determine the relationship between neutrophils and overall survival in lung cancer patients. The effect of neutrophils on lung cancer was determined using the Transwell migration assay, a proliferation assay, and a murine tumor model. Gene knockdown was used to determine poly ADP-ribose polymerase (PARP)-1 function in lung cancer-educated neutrophils. Western blot analysis and gelatin zymography were used to demonstrate the correlation between PARP-1 and matrix metallopeptidase 9 (MMP-9). Immunoprecipitation coupled to mass spectrometry (IP/MS) was used to identify the proteins interacting with PARP-1. Co-immunoprecipitation (Co-IP) was used to confirm that PARP-1 interacts with arachidonate 5-lipooxygenase (ALOX5). Neutrophil PARP-1 blockage by AG14361 rescued neutrophil-promoted lung cancer progression.

Results: An increased number of infiltrating neutrophils was negatively associated with overall survival in lung cancer patients (P < 0.001). Neutrophil activation promoted lung cancer cell invasion, migration, and proliferation in vitro, and murine lung cancer growth in vivo. Mechanistically, PARP-1 was shown to be involved in lung cancer cell-induced neutrophil activation to increase MMP-9 expression through interacting and stabilizing ALOX5 by post-translational protein modification (PARylation). Blocking PARP-1 by gene knockdown or AG14361 significantly decreased ALOX5 expression and MMP-9 production, and eliminated neutrophil-mediated lung cancer cell invasion and in vivo tumor growth.

Conclusions: We identified a novel mechanism by which PARP-1 mediates lung cancer cell-induced neutrophil activation and PARylates ALOX5 to regulate MMP-9 expression, which exacerbates lung cancer progression.

Cancer stem cells (CSCs) are a small subset of cells in cancers that are thought to initiate tumorous transformation and promote metastasis, recurrence, and resistance to treatment. Growing evidence has revealed the existence of CSCs in various types of cancers and suggested that CSCs differentiate into diverse lineage cells that contribute to tumor progression. We may be able to overcome the limitations of cancer treatment with a comprehensive understanding of the biological features and mechanisms underlying therapeutic resistance in CSCs. This review provides an overview of the properties, biomarkers, and mechanisms of resistance shown by CSCs. Recent findings on metabolic features, especially fatty acid metabolism and ferroptosis in CSCs, are highlighted, along with promising targeting strategies. Targeting CSCs is a potential treatment plan to conquer cancer and prevent resistance and relapse in cancer treatment.

Immunotherapy represents a promising strategy for cancer treatment that utilizes immune cells or drugs to activate the patient's own immune system and eliminate cancer cells. One of the most exciting advances within this field is the targeting of neoantigens, which are peptides derived from non-synonymous somatic mutations that are found exclusively within cancer cells and absent in normal cells. Although neoantigen-based therapeutic vaccines have not received approval for standard cancer treatment, early clinical trials have yielded encouraging outcomes as standalone monotherapy or when combined with checkpoint inhibitors. Progress made in high-throughput sequencing and bioinformatics have greatly facilitated the precise and efficient identification of neoantigens. Consequently, personalized neoantigen-based vaccines tailored to each patient have been developed that are capable of eliciting a robust and long-lasting immune response which effectively eliminates tumors and prevents recurrences. This review provides a concise overview consolidating the latest clinical advances in neoantigen-based therapeutic vaccines, and also discusses challenges and future perspectives for this innovative approach, particularly emphasizing the potential of neoantigen-based therapeutic vaccines to enhance clinical efficacy against advanced solid tumors.

Lung cancer is the most common and fatal malignant disease worldwide and has the highest mortality rate among tumor-related causes of death. Early diagnosis and precision medicine can significantly improve the survival rate and prognosis of lung cancer patients. At present, the clinical diagnosis of lung cancer is challenging due to a lack of effective non-invasive detection methods and biomarkers, and treatment is primarily hindered by drug resistance and high tumor heterogeneity. Liquid biopsy is a method for detecting circulating biomarkers in the blood and other body fluids containing genetic information from primary tumor tissues. Bronchoalveolar lavage fluid (BALF) is a potential liquid biopsy medium that is rich in a variety of bioactive substances and cell components. BALF contains information on the key characteristics of tumors, including the tumor subtype, gene mutation type, and tumor environment, thus BALF may be used as a diagnostic supplement to lung biopsy. In this review, the current research on BALF in the diagnosis, treatment, and prognosis of lung cancer is summarized. The advantages and disadvantages of different components of BALF, including cells, cell-free DNA, extracellular vesicles, and microRNA are introduced. In particular, the great potential of extracellular vesicles in precision diagnosis and detection of drug-resistant for lung cancer is highlighted. In addition, the performance of liquid biopsies with different body fluid sources in lung cancer detection are compared to facilitate more selective studies involving BALF, thereby promoting the application of BALF for precision medicine in lung cancer patients in the future.

Objective: DNA damage response (DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation (DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor (ICI) therapy in gastrointestinal (GI) cancer.

Methods: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts.

Results: The DRIA signature includes three genes (CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients (81.8% vs. 8.8%; P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve (AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein-Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer.

Conclusions: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pan-cancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.

Objective: This study evaluated the safety and efficacy of an anti-epidermal growth factor receptor (EGFR) antibody (SCT200) and an anti-programmed cell death 1 (PD-1) antibody (SCT-I10A) as third-line or subsequent therapies in patients with rat sarcoma viral oncogene (RAS)/v-raf murine sarcoma viral oncogene homolog B (BRAF) wild-type (wt) metastatic colorectal cancer (mCRC).

Methods: We conducted a multicenter, open-label, phase Ib clinical trial. Patients with histologically confirmed RAS/BRAF wt mCRC with more than two lines of treatment were enrolled and treated with SCT-I10A and SCT200. The primary endpoints were the objective response rate (ORR) and safety. The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

Results: Twenty-one patients were enrolled in the study through January 28, 2023. The ORR was 28.57% and the DCR was 85.71% (18/21). The median PFS and OS were 4.14 and 12.84 months, respectively. The treatment-related adverse events (TRAEs) were tolerable. Moreover, compared with the monotherapy cohort from our previous phase I study evaluating SCT200 for RAS/BRAF wt mCRC in a third-line setting, no significant improvements in PFS and OS were observed in the combination group.

Conclusions: SCT200 combined with SCT-I10A demonstrated promising efficacy in previously treated RAS/BRAF wt mCRC patients with an acceptable safety profile. Further head-to-head studies with larger sample sizes are needed to validate whether the efficacy and safety of combined anti-EGFR and anti-PD-1 therapy are superior to anti-EGFR monotherapy in the third-line setting. (Registration No. NCT04229537).

Intestinal flora affects the maturation of the host immune system, serves as a biomarker and efficacy predictor in the immunotherapy of several cancers, and has an important role in the development of colorectal cancer (CRC). Anti-PD-1/PD-L1 antibodies have shown satisfactory results in MSI-H/dMMR CRC but performed poorly in patients with MSS/pMMR CRC. In recent years an increasing number of studies have shown that intestinal flora has an important impact on anti-PD-1/PD-L1 antibody efficacy in CRC patients. Preclinical and clinical evidence have suggested that anti-PD-1/PD-L1 antibody efficacy can be improved by altering the composition of the intestinal flora in CRC. Herein, we summarize the studies related to the influence of intestinal flora on anti-PD-1/PD-L1 antibody efficacy in CRC and discuss the potential underlying mechanism(s). We have focused on the impact of the intestinal flora on the efficacy and safety of anti-PD-1/PD-L1 antibodies in CRC and how to better utilize the intestinal flora as an adjuvant to improve the efficacy of anti-PD-1/PD-L1 antibodies. In addition, we have provided a basis for the potential of the intestinal flora as a new treatment modality and indicator for determining patient prognosis.