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Neoadjuvant PD-1 blockade plus chemotherapy induces a high pathological complete response rate and anti-tumor immune subsets in clinical stage III gastric cancer.

ABSTRACT: First-line PD-1 blockade plus chemotherapy significantly improves the survival benefits in late-stage gastric cancer (GC) patients. However, the pathological response rate and effects on the immune microenvironment of neoadjuvant PD-1 blockade plus chemotherapy in patients with cTNM-stage III GC remain to be elucidated. Patients with cTNM-stage III GC who underwent neoadjuvant PD-1 blockade plus chemotherapy and surgery were enrolled. Four in vivo models bearing GC were jointly established to investigate the specific roles of chemotherapy and PD-1 blockade for GC treatment. The tumor immune microenvironment was analyzed by hematoxylin and eosin (H&E) and IHC staining, multicolor flow cytometry and immunofluorescence. A total of 75 patients with cTNM-stage III (cT2-4N1-3M0) gastric cancer who received neoadjuvant PD-1 blockade plus chemotherapy (SOX/XELOX) were included in this study. After treatment, 21 (28.0%) and 57 (76.0%) patients achieved pathological complete response (pCR) and post-therapy pathological downstaging. Subgroup analyses revealed that patients with CPS >1 (32.6% vs 8.3%) and dMMR (35.7% vs 25.4%) subtype had better efficacy. Additionally, the resected specimens showed more anti-tumor immune infiltration indicating a response to neoadjuvant PD-1 blockade plus chemotherapy. Multicolor immunofluorescence and in vivo experiments on mouse models revealed that elevated M1/M2 ratio of macrophages, CD8 + T cells and plasma cells indicated effective response to treatment. Furthermore, neoadjuvant PD-1 blockade plus chemotherapy neither delayed surgery nor increased postoperative complication rate. The analyses indicate neoadjuvant PD-1 blockade plus chemotherapy is a promising therapeutic strategy in patients with cTNM-stage III GC with an encouraging pCR rate.

SUBMITTER: Tang X

PROVIDER: S-EPMC9578498 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Neoadjuvant PD-1 blockade plus chemotherapy induces a high pathological complete response rate and anti-tumor immune subsets in clinical stage III gastric cancer.

Tang Xiaohuan X Li Mengyuan M Wu Xiaolong X Guo Ting T Zhang Li L Tang Lei L Jia Fangzhou F Hu Ying Y Zhang Yan Y Xing Xiaofang X Shan Fei F Gao Xiangyu X Li Ziyu Z

Oncoimmunology 20221014 1

First-line PD-1 blockade plus chemotherapy significantly improves the survival benefits in late-stage gastric cancer (GC) patients. However, the pathological response rate and effects on the immune microenvironment of neoadjuvant PD-1 blockade plus chemotherapy in patients with cTNM-stage III GC remain to be elucidated. Patients with cTNM-stage III GC who underwent neoadjuvant PD-1 blockade plus chemotherapy and surgery were enrolled. Four <i>in vivo</i> models bearing GC were jointly establishe ...[more]

PMID: 36268179

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Project description:BackgroundThe response of gastric cancer (GC) patients to first-line programmed cell death 1 (PD-1) blockade and S-1 plus oxaliplatin (SOX) chemotherapy varies considerably, and the underlying mechanisms driving this variability remain elusive. Exosomal microRNAs (miRNAs or miRs) have emerged as potential biomarkers for efficacy prediction due to their roles in GC biology and stable expression in serum. In this study, we aimed to identify biomarkers to predict patients' response to anti-PD-1 therapy and further elucidate the potential mechanisms by which these exosomal miRNAs modulate the immune response in GC.MethodsSerum exosomes were extracted from 11 GC patients (five in the primary cohort and six in the validation cohort) treated with SOX and camrelizumab (a PD-1 inhibitor). High-throughput sequencing was performed to identify miRNA expression profiles, after which hierarchical clustering and a differential expression analysis were conducted. Functional enrichment analyses of the target genes for the significantly upregulated miRNAs were performed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The validation of the candidate miRNAs was carried out by quantitative polymerase chain reaction (qPCR) in an independent cohort.ResultsMiRNA sequencing identified 3,083 miRNAs, of which 74 (42 upregulated and 32 downregulated) were differentially expressed between the responders and non-responders. The GO and KEGG pathway analyses of the top 20 upregulated miRNAs indicated that the target genes were significantly involved in transcription regulation, cytoplasmic processes, and protein binding, and that key pathways included the PI3K-AKT, MAPK, RAP1, and RAS signaling pathways. Consistent with the sequencing findings, the qPCR validation results showed significant differences in the expression levels of miRNA451a and miRNA142-5p between the responders and non-responders.ConclusionsThis study identified specific plasma exosomal miRNAs in GC patients that differ between responders and non-responders to PD-1 monoclonal antibody therapy combined with chemotherapy. These miRNAs could serve as predictive biomarkers, paving the way for precision medicine and personalized therapy in the treatment of GC.

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Neoadjuvant PD-1 blockade plus chemotherapy induces a high pathological complete response rate and anti-tumor immune subsets in clinical stage III gastric cancer.

Publications

Neoadjuvant PD-1 blockade plus chemotherapy induces a high pathological complete response rate and anti-tumor immune subsets in clinical stage III gastric cancer.

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