Chemotherapy efficacy is a pivotal concern in the treatment of various malignancies, as it directly impacts patient outcomes and overall survival, progression remains the leading clinical problem [3, 6]. In our study, we aimed to investigate factors associated with disease progression (PD) in NSCLC patients undergoing chemotherapy.
Previous studies have highlighted the role of the tumor microenvironment (TME) in cancer chemotherapy [7, 29]. However, some studies have also indicated that the status of the immune microenvironment within the tumor site and the overall systemic immune profiles of cancer patients before initiating treatment may impact their response to chemotherapy[31]. In recent years, a substantial body of research has indicated that immunological markers in peripheral blood, such as lower PBMC counts and reduced levels of cytokine expression, have been associated with poorer treatment responses. [11, 18, 22, 23]. In light of these findings, we conducted a comparative analysis of peripheral blood routine parameters, specifically white blood cell (WBC), neutrophil, and lymphocyte counts, between the PD group (n = 21) and the Non-PD group (n = 68). Our results revealed a significant decrease in WBC counts among patients who experienced disease progression compared to those in the Non-PD group with relatively stable disease status(P = 0.028).
This discovery opens up new possibilities for harnessing ATP detection as a sensitive and specific biomarker to predict disease progression. Most of the cell functions are dependent on the production of ATP and intracellular synthesis of ATP is a marker of cell activity[1]. In early studies, Cylex's Immuknow, employed this principle to assess the activity of CD4+ T lymphocytes[13]. Measuring the activity levels of CD4+ T lymphocytes in the peripheral blood of patients to early identify the potential risks of rejection and infection in organ transplant recipients[21]. In sepsis, some studies have reported significantly higher sATPCD4 of survivors compared to non-survivors within the first day of ICU admission[14, 32]. These contrasting results indicate the complexity of sATPCD4 and its potential implications in different disease states. Our study revealed that after chemotherapy, the sATP levels significantly decreased in the PD group, while, surprisingly, they exhibited a significant increase in the Non-PD group with stable disease status (Fig. 4). Additionally, we found significantly lower levels of both nATPCD4 and sATPCD4 in patients who experienced disease progression compared to the Non-PD group (P = 0.002, P < 0.0001) (Fig. 3). These results demonstrate that ATP can reflect the impact of chemotherapy on the immune function in NSCLC.
As an integral component of the anti-tumor immunity, peripheral blood CD4+ T cells help regulate and promote priming, migratory potential, and killing activity of CTL[10]. The results of the ROC curve analysis demonstrated an area under the curve (AUC) of 0.887 for sATPCD4, significantly higher than WBC (AUC = 0.660) and nATPCD4 (AUC = 0.713). Using a cutoff value of 224.5 ng/ml for sATPCD4, the sensitivity and specificity were determined to be 77.4% and 88.2%(Fig. 5). When ATP levels are below 224 ng/mL, there is a higher likelihood of disease progression in patients, indicating a strong correlation between CD4+ T cell immune function and patient prognosis. Patients with low ATP levels are in an immunosuppressed state, which accelerates tumor progression. This is due to the immunosuppressive network formed by the interaction between cancer cells and host immune cells, which promotes tumor growth and shields tumor cells from immune attacks[33, 36]. Despite the involvement of different CD4+ T cell subsets in tumor promotion and rejection during the immune editing process,sATPCD4 reflect the net status of immune activity[21].
In addition, this study also demonstrates that sATPCD4 is an independent risk factor influencing disease progression, particularly when sATPCD4 levels fall below 224.5 ng/mL suggests that physicians should pay closer attention to tumor progression and the immunosuppressive state of patients with low ATP values in subsequent assessments. Previously, researchers conducted intervention therapy for liver transplant patients with hepatocellular carcinoma based on CD4+ T ATP values. Immunosuppressive agents were adjusted according to the ATP expression levels. The results showed that patients in the intervention group had a significantly higher one-year survival rate than those in the control group[19]. Increasing evidence suggests the growing importance of CD4+ T cells in mediating tumor immune surveillance, immune therapy response, and cancer prognosis[28]. Sustained and effective antitumor immune responses necessitate the involvement of CD4+ T cells, which enhance CD8+ T effector responses through the secretion of cytokines like interleukin-2, participate in direct antitumor actions via interferon-gamma and tumor necrosis factor, or promote B cell antibody-mediated humoral responses through CD40 ligand binding[25]. The potential value of CD4+ T-cell immune function in the assessment of therapeutic efficacy cannot be underestimated.
It is important to acknowledge the limitations of this study, firstly, the relatively small sample size and limited number of events in our study prevented comprehensive multivariable analyses and draw definitive conclusions. It was conducted retrospectively with manual data extraction and entry, which introduces the possibility of data entry errors and patient selection bias. Although this was a single-center study, all consecutive patients treated with Chemotherapy during the specified period were included, minimizing the potential for selection bias. Finally, considering that the benefit to PFS and OS is the main goal of immunotherapy for NSCLC patients, future research must extend the observation time and treatment cycles, and monitor the changes in sATPCD4 subsets longitudinally to explore their correlation with OS and PFS.
In summary, there is a strong correlation between low levels of nATP CD4 and sATP CD4 and tumor progression in advanced NSCLC patients undergoing chemotherapy, indicating their potential utility as valuable indicators. These findings may assist physicians in assessing the immune function to understand patients' immunological status, thereby adjusting treatment plans to prevent disease progression. However, further prospective studies with larger sample sizes and multicenter participation are needed to validate our results.