Analyzing protein expression in peripheral blood offers a minimally invasive and accessible approach for monitoring biomarkers during neoadjuvant immunotherapy. To our knowledge, this is the first study analyzing changes in plasma protein levels before and after neoadjuvant immunotherapy for gastric cancer. We identified two markers with distinct prognostic significance within the gastric cancer immunotherapy neoadjuvant clinical trial cohort. Notably, CD8A exhibited increased expression in the T1 group after neoadjuvant therapy and were positively correlated with the efficacy of immunoinfiltrating cells, including monocytes, macrophages, TNK cells, CD8 cells. Conversely, the expression of PGF demonstrated significant increased in the T2 group, correlating with the tumor regression grade of neoadjuvant therapy.
A growing body of evidence suggested the involvement of chemokines in the pathogenesis of various malignancies, including gastric cancer[13]. CD8A is a member of T cytotoxic pathway-related genes and encodes the CD8 antigen that is a cell surface glycoprotein found on most cytotoxic T cells. The CD8 antigen acts as a coreceptor with the T-cell receptor on the T cell to recognize antigens displayed by an antigen-presenting cell in the context of class I MHC molecules. CD8A expression may be a useful and measurable predictive marker of immunotherapeutic response and immune cell infiltration[14]. A previous study for pan-cancer has reported that high status of CD8A with high expression of PD-L1 might be a predictive marker of immunotherapeutic response[15]. Previous study also revealed the protective role of CD8A in the prognoses of hepatocellular carcinoma, metastatic melanoma, head and neck squamous cell carcinoma and bladder Cancer[16–19]. However, few studies clarified the association between CD8A and immunotherapeutic response in gastric cancer, so we further investigated the prognostic value of CD8A in cancer patients treated with immunotherapy in TCGA dataset. Our results showed that low CD8A expression was associated with poor survival outcomes among cancer patients treated with immunotherapy. Thus, CD8A can not only be a useful prognostic factor in gastric cancer patients but also a predictive marker of immunotherapeutic response in cancer patients treated with immunotherapy.
PGF is well known as a member of the VEGF family, which is active in angiogenesis and endothelial cell growth, exerting an effect on its proliferation and migration. PGF has been reported as a potent stimulator in cancer invasion by activating angiogenesis[20]. In addition, the overexpression of PGF is correlated with tumor stage, cancer progression and metastasis[21]. In colorectal cancer, Kaplan–Meier curve analysis showed that higher expression of the PGF gene was associated with a lower survival rate. The in vitro expression of PGF was consistent with bioinformatics results[22]. Similar results were obtained in our study that PGF expressed markedly highly in gastric cancer and played a role as an oncogene.
Our study revealed that, CD4+ T cells and monocytes increased in the T1 group after treatment, while CD8+ T cells and B cells decreased in the T2 group after treatment. The use of immune cell infiltration as a novel biomarker for predicting the prognosis of patients with various types of cancer holds great promise[23, 24]. While previous reports have implicated immune infiltration in affecting tumor patient prognosis[25–27], the interaction mechanism between prognosis and the tumor microenvironment remains incompletely understood. Neutrophils play a pivotal role in tumor formation and metastasis, exhibiting a dual role in inhibiting and promoting cancer[28, 29]. The mechanism of cancer progression is intricately linked to inflammation. Our evaluation of immune cell expression in different tumor microenvironments revealed higher expression levels of monocytes and neutrophils in the T2 group compared to the T1 group. Additionally, the infiltration of CD8+ T cells, NK cells, and B cells was lower in the T2 group, whereas memory CD4+ T cells increased in both groups. Elevated leukocyte levels in the blood significantly correlate with short survival and cancer cell metastasis in patients with non-hematologic malignancies, primarily attributed to an increase in mature polymorphonuclear cells[30]. B cells play a crucial role in humoral immunity, inhibiting the progression of tumor cells by secreting immunoglobulin and promoting T cell responses[31, 32]. The heightened presence of inflammatory cells can induce the production and secretion of various chemokines and cytokines, serving as inflammatory mediators that recruit more inflammatory cells to the tumor microenvironment, thereby exacerbating a vicious cycle.
According to the results of this study, when treated with neoadjuvant immunotherapy using sintilimab in combination with FLOT protocol of gastric cancer patients, we can use Human ELISA Kit to detect the expression levels of CD8A and PGF before and after neoadjuvant therapy, evaluate and predict the possible response to therapy, and conduct dynamic monitoring of blood after treatment (for example, every 3–6 months) to better predict the progression of the disease. The present study has some limitations. First, we did’t sequence tissue samples in the tumor microenvironment, which will require additional mechanistic analysis in the future. Second, the number of gastric/gastroesophageal samples in our center is small. A larger number of gastric adenocarcinoma patients with pre- and post-operative RNA sequences need to be collected to further evaluate the performance of gastric adenocarcinoma models in predicting the expression of these molecules.
In conclusion, our study comprehensively assessed plausible carcinogenic pathways and identified novel associations with gastric/gastroesophageal diagnosis and prognosis. Our data suggest that neoadjuvant therapy efficacy may be reflected by alterations in specific proteins, offering potential etiological and clinical implications. The molecular aspects of tumor regression after neoadjuvant chemotherapy are currently under investigation, and our findings indicate that the promising candidate markers CD8A and PGF are strongly associated with immune invasion, potentially providing novel treatment strategies for patients with gastric adenocarcinoma.