Immune checkpoint co-expression combined with systemic inflammatory index: A promising approach in prognostic evaluation of lymphoma in Egypt

Abstract

This editorial highlights a study which examines immune checkpoint markers and inflammation indices in lymphoproliferative neoplasms in Egypt. A study by Sherief et al, published in World Journal of Clinical Oncology, present a novel combination of prognostic markers, showing that co-expression levels of programmed death-ligand 1/C-X-C motif chemokine receptor 3 (CXCR3) and programmed death-1 (PD-1)/CXCR3 were significantly elevated, particularly PD-1/CXCR3 in stage IV lymphoma (area under the curve = 0.959). The systemic inflammatory response index (SIRI) increased in late-stage patients (area under the curve = 0.846) but decreased after treatment (P < 0.001). The study challenges previous beliefs regarding SIRI and PD-1/CXCR3’s impact on survival rates. Importantly, SIRI relies only on routine blood test data, making it feasible for use in resource-limited settings. This research establishes an immune-inflammatory biomarker system for lymphoma in areas with high hepatitis C virus prevalence in Egypt and offers a low-cost, effective prognostic model for better patient stratification and improved cancer healthcare equity.

Key Words: Lymphoproliferative neoplasms; Immune checkpoint; Co-expression; Systemic inflammatory response index; Prognostic biomarker; Hepatitis C virus; Resource-limited settings; Therapeutic monitoring

Core Tip: This editorial highlights a novel prognostic model that combines immune checkpoint co-expression and the systemic inflammatory response index. Notably, programmed death-ligand 1/C-X-C motif chemokine receptor 3 co-expression accurately identifies stage IV lymphoma, while systemic inflammatory response index effectively distinguishes advanced disease and decreases with effective treatment. This low-cost biomarker system improves patient stratification, supports treatment monitoring, and promotes healthcare equity in resource-constrained settings.

This editorial refers to "Prognostic significance of PD-L1/PD-1 co-expression and CXCR3-driven inflammatory signatures in Egyptian patients with lymphoproliferative neoplasms" by Sherief et al, 2026; https://dx.doi.org/10.5306/wjco.v17.i1.112801.

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INTRODUCTION

Lymphoproliferative neoplasms (LPNs), encompassing chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma, represent a heterogeneous group of hematological malignancies with substantial global morbidity and mortality[1]. In Egypt, the burden of LPNs is particularly pronounced, with non-Hodgkin lymphoma ranking among the top five malignancies and exhibiting an incidence rate nearly double the global average[2]. This elevated incidence is closely linked to endemic hepatitis C virus (HCV) infection, environmental risk factors, and delayed clinical presentation, which often result in advanced disease stages and poor treatment outcomes[3]. Despite advancements in chemotherapy, immunotherapy, and hematopoietic stem cell transplantation, the clinical course of LPNs remains unpredictable, highlighting the urgent need for reliable prognostic biomarkers to guide personalized management[4].

Immune checkpoint molecules, such as programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1), have emerged as critical regulators of tumor immune escape in hematological malignancies[5]. The PD-1/PD-L1 axis suppresses the function of cytotoxic T cells, enabling tumor cells to evade immune surveillance and promoting disease progression[6]. Concurrently, the C-X-C motif chemokine receptor 3 (CXCR3) plays a dual role in LPN pathogenesis: While it initially orchestrates anti-tumor immune responses by recruiting T-helper 1 cells, its overexpression can support tumor cell survival, proliferation, and metastasis[7]. Systemic inflammatory indices, including the systemic immune-inflammation index (SII) and systemic inflammatory response index (SIRI), have also gained attention as cost-effective and reproducible prognostic tools, reflecting the intricate crosstalk between systemic inflammation and tumor progression[8,9]. It is noteworthy that SIRI is calculated as (neutrophil count × monocyte count)/Lymphocyte count, and the reported values (e.g., a decrease from 250.7 to 5.0 post-treatment) are contingent upon local laboratory reference ranges and units. This striking change underscores its dynamic nature but should be interpreted within the specific clinical and laboratory context of the study.

However, data on the integration of immune checkpoint co-expression, CXCR3-driven inflammatory signatures, and systemic inflammatory indices in Egyptian patients with LPNs remain scarce. Most previous studies in the region have focused on epidemiology or treatment outcomes, with limited exploration of the prognostic potential of combined immunological and inflammatory biomarkers[10]. This knowledge gap is particularly critical in resource-limited settings, where access to advanced diagnostic modalities such as positron emission tomography-computed tomography (CT) or next-generation sequencing is often limited.

The study by Sherief et al[11], published in World Journal of Clinical Oncology, addresses this unmet need through a comprehensive case-control analysis of 90 Egyptian LPN patients and 90 matched healthy controls. By evaluating PD-L1/PD-1 co-expression with CXCR3, the authors identified the expression of CXCR3 on monocyte subsets and lymphocytes, as well as SII or SIRI, which correlated with disease stage, treatment response, and survival. Their findings demonstrate that PD-L1/CXCR3, PD-1/CXCR3, and SIRI exhibit high accuracy in identifying stage IV disease and independently predict overall survival (OS) and event-free survival (EFS). Furthermore, the post-treatment reduction in key biomarkers, such as PD-L1/CXCR3 and SIRI, highlights their potential as dynamic tools for therapeutic monitoring. This editorial aims to contextualize the significance of Sherief et al’s work[11] within the broader landscape of LPN prognostication, emphasizing its relevance for resource-limited settings. We discuss the clinical implications of integrating immune-inflammatory biomarkers into routine practice, address the study’s strengths and limitations, and outline future directions to validate and expand upon these findings.

IMPORTANT FINDING OF CO-EXPRESSION OF IMMUNE CHECKPOINT AND CXCR3

The co-expression of CXCR3 and PD-1/PD-L1 has potential value in the prognostic evaluation of proliferative lymphoma. CXCR3 enhances immune surveillance function by mediating the migration of effector T cells into the tumor microenvironment[12]. The PD-1/PD-L1 signaling pathway promotes immune escape by inhibiting T cell activity[13]. The co-expression of the two may reflect the dynamic imbalance of the tumor immune microenvironment, a characteristic state in which tumor immune escape and anti-tumor immune “exhaustion” coexist.

Several studies show that the CXCR3 chemokine system is vital for the effectiveness of anti-PD-1 immunotherapy[14]. In tumor-bearing mice treated with PD-1 inhibitors, the CXCR3-CXCL9 axis plays a key role in enhancing CD8⁺ T cell responses and guiding dendritic cell trafficking[15,16]. Additionally, CXCR3 promotes the accumulation of immunosuppressive CXCR3⁺ Tregs in tumors, which impairs CD8⁺ T cell function[17]. Changes in CXCR3⁺ T cells in peripheral blood after PD-1 inhibitor treatment may also serve as a prognostic indicator in cancer patients[18]. Strengthening CXCR3 signaling could improve anti-PD-1 treatment strategies. Preclinical studies have shown that CXCR3⁺ PD-1⁺ T cell subsets are enriched in tumor-infiltrating lymphocytes, and their proportion is positively correlated with PD-1 monoclonal antibody therapy response in murine tumors[15]. A similar mechanism has been validated in the study of PD-1-related inflammatory arthritis, where the CXCL10-CXCR3 axis forms a pro-inflammatory cycle with PD-1⁺ T cells[19]. In hematological tumors, immune-inflammatory markers such as lymphocyte/monocyte ratio and CD4/CD8 ratio are significantly correlated with the prognosis of multiple myeloma[20], suggesting that CXCR3 PD-1 co-expression may serve as a similar biomarker.

Sherief et al[11] found that the co-expression levels of immune checkpoint 1 (PD-L1/PD-1) and CXCR3 were significantly elevated in patients with advanced (stage IV) lymphoma, and were significantly correlated with shorter OS and EFS. As showed in Table 1, we systematically summarize and describe the findings of Sherief et al[11] for the co-expression profiles of immune checkpoint molecules (PD-1, PD-L1) and chemokine receptor CXCR3 in T cells and tumor cells. This elucidates the different co-expression patterns, their prognostic significance, their association with T cell exhaustion and tumor immune escape, and the strength of supporting evidence.

Table 1 Co-expression of PD-1/C-X-C motif chemokine receptor 3 or PD-L1/C-X-C motif chemokine receptor 3 in T cells and tumor cells. Expression patterns, clinical significance, and evidence strength.

Cell type	Co-express pattern	Significance	Evidence
T cells	Programmed death-1/CXCR3, PD-L1/CXCR3	Strong adverse prognostic markers (associated with advanced disease and short survival). Reflect the exhaustion status and dysfunction of T cells. Dynamic changes can indicate treatment response	Strong; provided specific flow cytometry data, statistical analysis (receiver operating characteristic, survival analysis, multivariate regression), and mechanism discussion
Tumor cells	PD-L1/CXCR3	PD-L1 expression mediates immune escape. Overexpression of CXCR3 may promote tumorigenesis. The two may synergistically promote an immunosuppressive microenvironment	Indirect/inferential; the significance is based on known literature and article background discussion, lacking direct experimental data on co- expression on tumor cells in this article

CXCR3: C-X-C motif chemokine receptor 3; PD-L1: Programmed death-ligand 1.

Furthermore, inflammatory indices, such as SII and SIRI, are also important indicators of OS and EFS in LPN patients. As shown in Figure 1, PD-L1/PD-1 co-expression with CXCR3, combined with SII and SIRI, constitutes a practical prognostic panel for staging and outcome prediction in Egyptian patients with LPNs[11]. We hypothesize that the high co-expression of PD-L1/CXCR3 or PD-1/CXCR3 of T lymphocytes in the patient's blood or tumor microenvironment directly leads to weakened T-cell immune function and T-cell exhaustion, indirectly causing monocytes to develop into tumor-associated macrophages and affecting the recruitment and division of neutrophils, thereby promoting tumor growth and progression, ultimately resulting in a significant decrease in OS and EFS in patients.

Figure 1 Summary of key findings and clinical implications of the immune-inflammatory biomarker, such as programmed death-ligand 1/C-X-C motif chemokine receptor 3, programmed death-1/C-X-C motif chemokine receptor 3, systemic immune-inflammation index and systemic inflammatory response index, from Sherief et al[11]. A: Schematic overview of the integrated immune-inflammatory biomarker panel and its clinical implications in lymphoproliferative neoplasms; B: The survival at the endpoint for overall survival and event-free survival of patients with high expression of systemic immune-inflammation index, systemic inflammatory response index, programmed death-ligand 1/C-X-C motif chemokine receptor 3, and programmed death-1/C-X-C motif chemokine receptor 3 was shortened by 20%, 45%, 40% and 40%, and was reduced by 30%, 30%, 40% and 50%, respectively. These results indicate that when patients are diagnosed with lymphoproliferative neoplasms and have high co-expression of immune-inflammatory biomarkers, their prognosis is poor. Therefore, different strategies should be developed and adopted in clinical treatment for patients with high expression to improve efficacy. CXCR3: C-X-C motif chemokine receptor 3; EFS: Event-free survival; OS: Overall survival; PD-L1: Programmed death-ligand 1; PD-1: Programmed death-1; SII: Systemic immune-inflammation index; SIRI: Systemic inflammatory response index.

These biomarkers may guide personalized management and therapeutic monitoring. This discovery suggests that the co-expression of immune checkpoint molecule (PD-1) and CXCR3 on T cells may reflect the depletion of T cell function in the tumor microenvironment due to chronic inflammation, which is closely associated with poorer clinical outcomes.

DIAGNOSTIC EFFICACY AND DYNAMIC DETECTION VALUE OF THE SYSTEMIC INFLAMMATION INDEX

The SIRI has shown significant advantages in the diagnosis of stage IV lymphoma, and its clinical value has been verified. Research data show that the area under the curve value of SIRI reaches 0.846, which statistically suggests good discriminatory ability and can effectively distinguish lymphoma patients with different disease stages. Specifically, its sensitivity and specificity are as high as 78.95% and 71.43%, respectively, indicating that SIRI has favorable performance in identifying advanced lymphoma and can provide reliable diagnostic evidence for clinical doctors.

Multivariate analysis further strengthened the clinical significance of SIRI, and the results showed that high SIRI was an independent predictor of advanced lymphoma (odds ratio = 2.80, P = 0.005). This discovery highlights the crucial role of SIRI in disease progression assessment, which not only helps to identify high-risk patients early but also provides important references for developing personalized treatment plans. In addition, the dynamic changes of SIRI provide a new perspective for treatment monitoring. For example, after treatment, the SIRI level significantly decreased from 250.7 to 5.0, which not only reflects the effectiveness of the treatment but also provides an objective indicator for real-time evaluation of the patient’s response to treatment. This dynamic monitoring capability is consistent with the results of co-expression studies of PD-L1/PD-1 and CXCR3, which also reveal a close association between inflammatory markers and disease invasiveness.

From a clinical practice perspective, the application of SIRI has multiple advantages. Firstly, it is based on routine blood tests, with low cost and high reproducibility, making it suitable for promotion in resource-limited areas. Secondly, its detection method is simple and does not require complex equipment, and can be implemented by ordinary medical institutions. In addition, SIRI’s real-time feedback capability provides the possibility for optimizing treatment strategies, such as monitoring changes before and after treatment, allowing doctors to adjust treatment plans in a timely manner and improve treatment effectiveness. Therefore, SIRI not only helps with early diagnosis but also provides real-time feedback for treatment response, which has important clinical value. In the future, with the deepening of research, SIRI is expected to become an essential tool in the diagnosis and treatment of lymphoma, resulting in a better prognosis to patients. This is consistent with the observation results of another similar study on the co-expression of PD-L1/PD-1 and CXCR3, where patients in the co-expression group showed a significant increase in extranodal invasiveness[21,22].

BIOLOGICAL SIGNIFICANCE OF MONOCYTE SUBPOPULATION CXCR3 REPROGRAMMING

The reprogramming of monocyte subpopulation CXCR3 expression is closely related to the SIRI, revealing the deep regulatory mechanism of the tumor microenvironment on the immune system. In lymphoma patients, the expression of CXCR3 in classical monocytes (CD14⁺⁺CD16^-) is significantly downregulated, while the expression of CXCR3 in intermediate monocytes (CD14⁺⁺CD16⁺) is significantly upregulated[23]. This phenotypic shift not only reflects the systemic inflammatory response induced by tumors but also suggests adaptive remodeling of the innate immune system.

As the “frontline sentinel” of the immune system, the downregulation of CXCR3 expression in classical monocytes may weaken their ability to migrate to inflammatory sites[24], leading to impaired immune surveillance function in the tumor microenvironment. As an amplifier of inflammatory response, the upregulation of CXCR3 expression in intermediate monocytes may exacerbate tumor-associated inflammation; promote tumor cell escape, and progression. This reprogramming phenomenon is closely related to the staging of lymphoma, and the imbalance of CXCR3 expression is more significant in advanced patients, which may become a potential biomarker for evaluating the severity of the disease.

In addition, reprogramming of CXCR3 expression is also associated with patient survival prognosis. Research has shown that patients with high expression of intermediate monocyte CXCR3 have shorter progression-free survival, suggesting that it may serve as an indicator for predicting treatment response. Exploring its mechanism in depth is expected to provide new ideas for the precise diagnosis and treatment of lymphoma, especially in the development of targeted therapy strategies targeting the immune microenvironment, which is of great value. Future research needs to further validate the predictive efficacy of CXCR3 expression reprogramming in clinical practice, to promote the development of personalized therapies.

PRACTICAL PATH FOR OPTIMIZING RESOURCE ALLOCATION

In terms of technical feasibility, flow cytometry for detecting PD-1/CXCR3 co-expression is available in most medical centers, although its penetration and standardization can vary across resource-limited settings. In contrast, the calculation of SIRI relies solely on routine complete blood count parameters, offering significantly wider scalability and reproducibility with minimal infrastructure requirement. Wider adoption of immune phenotyping may require targeted capacity building and protocol harmonization initiatives to ensure consistent quality and interpretation across different laboratories. This technology can be independently completed by ordinary medical institutions without relying on high-end technology platforms or complex equipment, greatly improving the accessibility and convenience of testing. In addition, the detection results of flow cytometry are stable and reliable, which can provide an accurate diagnostic basis for clinical doctors.

This biomarker combination also supports dynamic monitoring, providing an objective and quantitative basis for efficacy evaluation through changes in biomarker levels before and after treatment. This dynamic monitoring capability not only helps to adjust treatment plans in a timely manner but also provides patients with a personalized treatment experience. In the clinical implementation process, this combination has no major obstacles and can smoothly integrate into the existing diagnosis and treatment process.

Overall, this biomarker combination combines economy, accessibility, and practicality, and is expected to become an important tool for lymphoma diagnosis and treatment. Its promotion and application will help promote the popularization of precision medicine, improve the diagnosis and treatment level of lymphoma, and provide patients with a better diagnosis and treatment experience. In the future, with the deepening of research and advances in technology, this combination is expected to play an important role in more medical scenarios.

INTERGRATION WITH ESTABLISHED PROGNOSTIC FRAMEWORKS

To contextualize the clinical utility of the proposed immune-inflammatory biomarker panel, it is essential to consider its relationship with established prognostic indices such as the International Prognostic Index or its subtype-specific variants. Future studies should aim to demonstrate whether the addition of PD-1/CXCR3 co-expression and SIRI provides incremental prognostic value, for instance, through improved risk discrimination or patient reclassification, beyond these conventional tools. Such evidence would be crucial for justifying its integration into routine clinical practice as a complementary risk-stratification module, particularly in settings where advanced imaging or molecular profiling is unavailable.

CLINICAL TRANSLATION/LIMITATIONS AND FUTURE DIRECTIONS

Based on the results of this study on the reprogramming of monocyte subpopulation CXCR3 expression, we strongly recommend promoting and validating its clinical application value in resource-limited areas. This biomarker detection has significant cost-effectiveness advantages, with low detection costs and simple operation procedures, requiring only routine blood samples and basic laboratory equipment to complete. This characteristic makes it particularly suitable for areas such as Egypt, where medical resources are relatively scarce, and often faces the dilemma of a shortage of advanced imaging equipment, such as positron emission tomography-computed tomography, complex operations, and high costs. By adopting this detection method, medical institutions can conduct preliminary screening and staging evaluation of lymphoma patients at a lower cost, providing an important reference for subsequent treatment decisions.

As an alternative or supplementary method, this detection method can effectively evaluate the staging and prognosis of lymphoma. In the absence of advanced imaging examinations, it can help doctors more accurately assess the degree of disease progression and develop more reasonable treatment plans. In addition, the study also found that these immune-inflammatory features can provide clues for screening patients suitable for immunotherapy (such as PD-1/PD-L1 inhibitors) by identifying specific immune microenvironment features. By analyzing the patient’s immune status, doctors can select treatment plans more accurately and improve treatment outcomes. To further improve prediction accuracy, we suggest exploring the possibility of integrating this detection method into existing prognostic models. By combining multiple biomarkers and clinical data, more comprehensive predictive models can be constructed to provide patients with more personalized treatment strategies.

It is essential to note that Sherief et al’s study[11] has several limitations, which need to be addressed in the future. Firstly, the single-center design and relatively short follow-up period (12 months) limit the generalizability of findings and the ability to assess long-term outcomes such as late relapse[25]. Multicenter prospective studies with extended follow-up are needed to validate the prognostic panel in diverse Egyptian populations and assess its performance across different treatment regimens[26]. Secondly, the study did not explore the functional mechanisms underlying the observed biomarker associations. For example, while PD-L1/CXCR3 co-expression correlates with poor survival, the specific role of exhausted CXCR3⁺PD-1⁺ T cells in LPN progression remains unclear[27]. Functional assays, such as cytokine profiling or in vitro T-cell exhaustion studies, could shed light on these mechanisms and identify potential therapeutic targets[28]. Additionally, integrating genomic data, such as mutations in myelocytomatosis oncogene, B-cell lymphoma 2, or TP53, with immune-inflammatory biomarkers may further refine risk stratification[25].

A key consideration for generalization is the study’s exclusion of patients with chronic viral infections (including HCV). Given the high prevalence of HCV in Egypt and its established link to lymphomagenesis, this exclusion may limit the direct applicability of the proposed biomarker panel to a substantial proportion of the Egyptian lymphoma population[29,30]. Therefore, validating these biomarkers in cohorts inclusive of HCV-positive patients constitutes a critical future direction. Furthermore, investigating the impact of HCV antiviral therapy on both inflammatory indices (such as SIRI) and immune checkpoint expression could provide insights into the interplay between chronic infection, inflammation, and lymphoma biology[30].

CONCLUSION

The study by Sherief et al[11] not only provides a potential lymphoma diagnosis and treatment framework for resource limited areas, but also lays the foundation for developing personalized treatment strategies. Its important clinical translational potential is expected to improve the diagnosis and treatment experience and prognosis of lymphoma patients worldwide. In summary, the immune inflammatory biomarker assessment framework pioneered by this study not only provides a new tool for prognostic management of lymphoproliferative tumors, but more importantly demonstrates a feasible model for precision medicine in resource constrained environments. With the advent of the immunotherapy era, this prognostic model based on routine testing is expected to provide a universal solution for individualized treatment of lymphoma worldwide. In the future, the focus should be on promoting its validation in prospective multicenter studies and exploring its implementation pathways in different healthcare systems, ultimately promoting the coordinated development of global cancer diagnosis and treatment levels.