Gastric cancer is the fifth most frequently diagnosed cancer and the fifth leading cause of cancer death worldwide, and the scale of the problem is matched by the difficulty of treating it. Because early gastric cancer typically produces no distinctive symptoms and many countries lack systematic screening programs, roughly seventy percent of patients are already diagnosed with locally advanced disease by the time the tumor is found. For these patients, the standard approach involves preoperative treatments, including neoadjuvant and conversion therapies, designed to shrink tumors, downstage the disease, and improve the chances of a complete surgical resection with clear margins, known as an R0 resection. Yet even with these advances, postoperative recurrence rates remain stubbornly high and prognosis remains poor, which is why identifying reliable markers of treatment response has become a central goal in gastric cancer research.

The new study focused on pathological complete response, or pCR, the total elimination of cancer cells in both the primary tumor and the dissected regional lymph nodes after preoperative treatment. In breast cancer and colorectal cancer, pCR is closely linked to disease-free survival and overall survival and is widely regarded as a potential surrogate marker for long-term benefit. The research team, building on their earlier work showing that systemic immune activity significantly influences the effectiveness of therapeutic interventions in gastric cancer, hypothesized that the overall state of the immune system, rather than just the local immune environment inside the tumor, might determine whether chemotherapy succeeds in wiping out the disease entirely.

Most tumor immunology research has concentrated heavily on the tumor microenvironment, the local ecosystem of immune and stromal cells surrounding the cancer within the tissue itself. But the systemic immune landscape, the activity of immune cells patrolling the entire body, is also correlated with cancer prognosis. Peripheral lymphocytes, particularly vital for immune surveillance, circulate in the bloodstream to detect and eliminate cancer cells, and alterations in lymphocyte subsets have been associated with prognosis in ovarian cancer, primary liver cancer, and breast cancer. In gastric cancer, peripheral inflammation markers such as the neutrophil-to-lymphocyte ratio, the platelet-to-lymphocyte ratio, and the systemic immune inflammation index have already been used to predict the effectiveness of preoperative chemotherapy and serve as prognostic biomarkers. However, these conventional ratios have limited predictive accuracy because they primarily reflect an underlying systemic pro-inflammatory status without identifying specific immune mechanisms, and there is no uniform standard definition for them. The predictive value of specific peripheral lymphocyte subsets for pCR in gastric cancer patients receiving preoperative chemotherapy remained unknown until now.

To address this gap, the researchers conducted a retrospective monocentric analysis of one hundred and seventy-three patients who underwent gastric resection between June 2014 and May 2023 at Zhongshan Hospital. All patients received preoperative chemotherapy followed by curative-intent resection with D2 lymph node dissection, and gastric adenocarcinoma was confirmed in every case. Peripheral blood samples were collected after the initial round of preoperative chemotherapy, and lymphocyte detection was performed using flow cytometry with a carefully defined panel of surface markers. The researchers measured five key subsets: CD3-positive T cells, CD8-positive cytotoxic T cells, CD4-positive helper T cells, CD19-positive B cells, and CD16-positive CD56-positive natural killer cells. Therapeutic response was evaluated according to RECIST 1.1 criteria, and pCR was defined as the absence of any remaining tumor component in the primary tumor and the dissected regional lymph nodes.

The results revealed a compelling pattern. Among all patients, only fifteen, or 8.7 percent, achieved pCR, while one hundred and fifty-eight remained non-pCR. When the researchers compared peripheral lymphocyte profiles between the two groups, they found that the ratio and absolute count of CD19-positive B cells were significantly lower in the pCR group compared with the non-pCR group. Conversely, the ratio and absolute count of CD16-positive CD56-positive natural killer cells were significantly higher in the pCR group. No statistically significant differences were observed between the two groups for the ratios and counts of CD4-positive T cells and CD8-positive T cells. Multivariate analysis confirmed that a higher B cell ratio was independently associated with poorer treatment response, with an odds ratio of 0.751 per one percent increase in B cell proportion. Receiver operating characteristic curve analysis identified an optimal B cell ratio cut-off of 7.250, with a sensitivity of 75.95 percent and a specificity of 66.67 percent in predicting which patients would achieve pCR.

The prognostic implications extended beyond treatment response into long-term survival. Patients with a high natural killer cell count, defined as more than 250 cells per microliter of peripheral blood, exhibited superior overall survival compared with those with a low count, with a hazard ratio of 1.991 and a p-value of 0.044 in univariate analysis. Other markers, including B cell count, CD4-positive T cell count, and CD8-positive T cell count, were assessed for their association with overall survival, but none reached statistical significance. While multivariate Cox regression analysis did not reach statistical significance for natural killer cell abundance, with a p-value of 0.074, the hazard ratio remained consistent in direction with the univariate analysis, suggesting that the effect may be partly mediated by other clinical covariates such as tumor burden or systemic inflammation, and that the analysis may have been underpowered. The researchers emphasize that validation in larger prospective cohorts is required before these findings can be translated into clinical practice.

To investigate the biological mechanisms underlying these associations, the team examined cytokine levels in the peripheral blood, including tumor necrosis factor, interleukin-8, soluble interleukin-2 receptor, and interleukin-6. Elevated levels of tumor necrosis factor and interleukin-8 after the initial chemotherapy cycle were associated with better treatment response, with patients achieving pCR showing mean concentrations of 29.4 picograms per milliliter for tumor necrosis factor compared with 11.8 in non-responders, and 42.3 picograms per milliliter for interleukin-8 compared with 20.6. Spearman correlation analysis revealed that B cell absolute count was weakly negatively correlated with tumor necrosis factor secretion, suggesting a potential immunosuppressive role for these cells. This finding aligns with previous research showing that CD19-positive regulatory B cells in gastric cancer can modulate the conversion of CD4-positive T cells into regulatory T cells by secreting interleukin-10 and transforming growth factor beta, and can impair the antitumor effect of helper T cells by inhibiting interferon-gamma and tumor necrosis factor alpha production.

The researchers also explored whether peripheral lymphocyte subsets mirror the immune landscape inside the tumor itself. Using computational deconvolution of transcriptomic data from an independent cohort of 433 gastric cancer patients from Yonsei University, they found that an increase in natural killer cell gene signatures was observed in tumors with low B cell infiltration, mirroring the inverse relationship seen in peripheral blood. Tumors with low natural killer cell infiltration showed increased macrophage M0 and regulatory T cell populations and decreased macrophage M1 and gamma-delta T cell populations, correlating with poor prognosis. High natural killer cell infiltration within the tumor microenvironment predicted significantly better survival outcomes, with a p-value of 0.049. These findings suggest that the peripheral blood immune profile may partly reflect immune cell densities within the tumor microenvironment, meaning that a simple blood test could potentially substitute for invasive tissue biopsies when assessing the tumor immune contexture.

The study has important limitations that the authors acknowledge candidly. The cohort included only fifteen pCR patients and one hundred and fifty-eight non-pCR patients, increasing the risk of sampling bias. Data on mature subsets of B cells and natural killer cells were incomplete, and the researchers did not evaluate the phenotypes and functions of these cells at the RNA and protein levels. The relationship between B cells and cytokines was not fully understood, and multifactorial analyses may introduce confounding variables. The researchers also did not analyze variables such as radiotherapy, hyperthermic intraperitoneal chemotherapy, or immunotherapy, and heterogeneous treatment regimens may confound immune biomarker associations. Finally, the cut-off values for peripheral lymphocyte subsets could differ based on the measurement methods used, potentially influencing the results. Despite these constraints, the study points toward a future where preoperative chemotherapy efficacy could be assessed noninvasively using peripheral lymphocyte subset markers, with a lower proportion of CD19-positive B cells serving as a predictive biomarker for pathological complete response and an increased peripheral natural killer cell count functioning as an auxiliary factor for risk stratification when combined with clinical parameters for assessing long-term outcomes in gastric cancer patients receiving preoperative chemotherapy.

Subject of Research: Peripheral Lymphocyte Subsets Predict Efficacy and Overall Survival in Gastric Cancer Patients Receiving Preoperative Chemotherapy: A Retrospective Cohort Study

Article Title: Peripheral Lymphocyte Subsets Predict Efficacy and Overall Survival in Gastric Cancer Patients Receiving Preoperative Chemotherapy: A Retrospective Cohort Study

Article References: Xue, Z., Liu, D., Sun, Z., Li, B., Liu, X., Zhao, J., Li, H., Wang, X., & Wang, Z. (2026). Peripheral Lymphocyte Subsets Predict Efficacy and Overall Survival in Gastric Cancer Patients Receiving Preoperative Chemotherapy: A Retrospective Cohort Study. Cancer Reports, 9(10), Article e70704. https://doi.org/10.1002/cnr2.70704

Image Credits: AI Generated

DOI: 10.1002/cnr2.70704

Keywords: Peripheral, Lymphocyte, Subsets, Predict, Efficacy, Overall, Survival, Gastric, Cancer, Patients, Receiving, Preoperative