Abstract
Objective
To explore the clinicopathological features and the prognostic values of the co-stimulatory molecules OX40 and the inducible T-cell co-stimulator (ICOS) in Extranodal Natural Killer/T-cell Lymphoma (ENKTL).
Methods
82 participants (median age 51 years, 26.8% female) were included in this study. OX40 and ICOS expression was detected using immunohistochemistry on paraffin‑embedded sections. The level of OX40 and ICOS expression was categorized into negative (0%, no staining) and positive groups. Kaplan-Meier analysis was used to estimate the probability of survival rates, and group comparisons were made using the Log-rank test.
Results
Positive staining for OX40 and ICOS was observed in 64 (78.0%) and 48 (58.5%) cases, respectively. The main differences between OX40-positive and OX40-negative were in the Chinese Southwest Oncology Group and Asia Lymphoma Study Group ENKTL (CA) stage, Korean Prognostic Index (KPI), CD68, PD1, PDL1, and CD152. Patients exhibiting positive OX40 expression demonstrated a statistically significant improvement in survival compared to the negative group (p < 0.001). However, no statistically significant survival difference was observed between ICOS-negative and ICOS-positive patients (p = 0.760). The expression of OX40 was a favorable prognostic indicator for ENKTL patients (Hazard Ratio = 0.049, 95% confidence interval: 0.009–0.285, p < 0.001) in multivariable analysis.
Conclusions
Our findings reveal that positive OX40 expression serves as an independent prognostic marker for improved survival of ENKTL, suggesting its potential utility in stratifying patient risk and optimizing treatment strategies. Future research should focus on the therapeutic targeting of OX40 in ENKTL.
Keywords: Extranodal Natural killer/T-Cell Lymphoma, inducible T-cell co-stimulator, OX40, prognosis
Introduction
Extranodal Natural Killer/T-cell Lymphoma (ENKTL) is an aggressive lymphoma predominantly found in East Asia and South America [1,2], and it is universally associated with Epstein-Barr virus (EBV) infection, which contributes to poor survival outcomes [3,4]. Non-anthracycline-based regimens have been widely used as the first-line treatment for ENKTL, providing significant therapeutic benefits [5]. Notably, L-asparaginase-based regimens have been shown to achieve complete remission rates of approximately 55% to 80% in patients with early stage ENKTL [6,7]. However, there remains a high incidence of resistance or relapse among patients in advanced stages, those at high risk, and those with high EBV loads. This situation highlights the importance of the tumor microenvironment, which significantly influences the progression of ENKTL through altered cytokine and chemokine expression, affecting immune dynamics. Within this immune microenvironment, the activation of T cells is crucial for anti-tumor immune responses, a process that relies on efficient co-stimulatory molecules and the regulation of immune checkpoints [8].
Immune checkpoints serve a crucial function in lymphoma, acting as key regulators in immune responses. These checkpoints, which encompass Programmed Death-1 (PD-1), Programmed Death-Ligand 1 (PD-L1), and Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), are vital mechanisms that modulate the immune system’s activity and response [9–12]. OX40 (also known as CD134) is a member of the tumor necrosis factor superfamily, playing a crucial role in promoting T-cell survival and regulating cytokine receptor signaling [13]. Inducible T-cell co-stimulator (also known as ICOS, CD278, AILIM, H4) is a costimulatory receptor for T-cell enhancement and a member of the B7/CD28 receptor superfamily [14]. Moreover, ICOS and OX40 are pivotal in the development and persistence of central memory T cells [15]. ICOS and OX40 not only enhance T cell activation, expansion, and survival but also contribute to the development of a robust and durable memory T cell response, essential for forming a long-term protective immunity pool [16]. In a retrospective study of 52 patients with Peripheral T-cell lymphoma, no significant survival differences were observed between individuals with positive versus negative OX40 expression [17]. Conversely, Lu et al. reported that high OX40 expression was associated with improved clinical outcomes in patients with diffuse large B-cell lymphoma (DLBCL) [18]. These findings suggest a complex and context-dependent role of co-stimulatory molecules in lymphoma pathogenesis and highlight the variability in their prognostic impact across different lymphoma subtypes. ENKTL is known for its aggressive behavior and unique immunological features compared to other lymphomas. However, the prognostic roles of OX40 and ICOS in ENKTL have not yet been explored. Therefore, this study aimed to evaluate the clinicopathological characteristics and the prognostic significance of OX40 and ICOS in ENKTL. By focusing on these co-stimulatory molecules, we aim to provide an understanding of their role in ENKTL, thereby contributing significantly to the development of targeted treatment strategies.
Material and methods
Patients
A total of 82 patients with pathologically confirmed ENKTL diagnosed at the Affiliated Hospital of Xuzhou Medical University from January 2011 to July 2020 were included. Exclusion criteria included patients with incomplete clinical records (e.g. the absence of essential immunohistochemistry data or missing baseline clinical characteristics) or a history of other malignancies. Among patients with evaluable treatment information, a variety of first-line therapeutic regimens were administered. Eleven patients received the DDGP regimen (dexamethasone, cisplatin, gemcitabine, and pegaspargase), six were treated with the SMILE regimen (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide), and another six received gemcitabine plus L-asparaginase-based therapies. Four patients were treated with pegaspargase- or L-asparaginase-based regimens alone. Additionally, eight patients received CHOP or CHOP-like regimens, and fifteen patients underwent radiotherapy. Ethics approval was obtained from the Ethics Committee of the Affiliated Hospital of Xuzhou Medical University (No. XYFY2022-KL363-01). All participants provided written informed consent. This study was conducted following the Declaration of Helsinki.
Immunohistochemistry
Clinicopathological variables and outcomes were obtained from the Pathology Department. Formalin-fixed, 4-µm thick, paraffin-embedded biopsy samples were collected at baseline. Immunohistochemical staining for ICOS (clone EPR20560), PD-1 (clone UMAB199, ready-to-use), and P53 (clone DO-7) was carried out using the EnVision immunohistochemistry kit, biotinylated secondary antibody working solution, and horseradish peroxidase (HRP) working solution. Ten fields were observed for ICOS and OX40 staining using a × 400 magnification microscope (×22 objective with ×10 eyepiece). Immunohistochemical staining for OX40 and ICOS was classified as negative when no staining was observed. Positive staining was defined as any detectable staining above background levels. The average percentage of positive tumor cells/stromal cells was calculated based on these observations. The expression of these biomarkers in each case was evaluated, correlating with clinicopathologic features.
Covariates
Covariates were selected based on previous literature [19–23]: age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), the presence of B symptoms, serum lactate dehydrogenase (LDH, U/L), and Epstein-Barr encoding region (EBER) status. The disease stage was divided according to the Ann Arbor classification system and the Chinese Southwest Oncology Group and Asia Lymphoma Study Group ENKTL (CA) system [24]. The CA system is specifically designed for ENKTL and provides improved prognostic relevance by accounting for extranodal spread and anatomical patterns typical of this disease.
Prognostic stratification was performed using four established indices: the Korean Prognostic Index (KPI), International Prognostic Index (IPI), Nomogram-Revised Index (NRI), and Prognostic Index of Natural Killer lymphoma (PINK). The KPI evaluates stage, B symptoms, serum LDH levels, and regional lymph node involvement.
The IPI incorporates age, ECOG performance status, LDH, stage, and the number of extranodal sites. The NRI is a nomogram-based scoring system tailored for NK/T-cell lymphoma, integrating clinical and laboratory parameters. The PINK is specifically developed for ENKTL and includes age >60, stage III/IV, non-nasal type, and distant lymph-node involvement. For each patient, the corresponding scores were calculated, and risk categories were assigned according to the original publications.
Follow-up
The patient’s status was confirmed by consulting the patient’s inpatient and outpatient medical record systems, and the follow-up method was conducted by telephone calls or self-return to the hospital for re-examination. Overall survival (OS) was calculated as the duration between the time of diagnosis and the date of death or the last follow-up. All patients were followed up until May 2023.
Statistical analysis
Baseline characteristics were presented as mean (standard deviation, SD) and n (%). Chi-square test and Mann-Whitney U test were utilized for the comparison of different groups. OS was evaluated using the Kaplan-Meier method, and group comparisons were made with the Log-rank test. Univariable and multivariable analyses were performed with Cox proportional hazards regression models. A stepwise regression approach, alternating between forward selection and backward elimination, was applied. The results were presented as hazard ratios (HRs) and 95% confidence intervals (CIs). All risk factors with a p < 0.05 in univariable analysis were included in the multivariable analysis. A Cox proportional hazards regression model with backward selection was used to identify risk factors.
All statistical analyses were performed by R software (version 4.2.2; http://www. Rproject.org). Statistical significance was set at a P value of < 0.05 (two-tailed).
Results
Baseline characteristics
A total of 82 participants were included in this study. The baseline characteristics were presented in Table 1. The median age was 51 years and 26.8% were female. The 5-y OS was 61.8% and the median follow-up time was 87.0 (95% CI: 77.5–96.4) months.
Table 1.
Clinicopathological differences between OX40-positive and negative cases.
| Variables | Overall (n = 82) |
Negative (n = 18) |
Positive (n = 64) |
P | |
|---|---|---|---|---|---|
| Age (mean (SD)) | 49.55 (18.07) | 45.67 (15.33) | 50.64 (18.73) | 0.305 | |
| Gender (%) | Male | 60 (73.2) | 14 (77.8) | 46 (71.9) | 0.843 |
| Female | 22 (26.8) | 4 (22.2) | 18 (28.1) | ||
| Ann Arbor Stage (%) | I/II | 73 (89.0) | 16 (88.9) | 57 (89.1) | >0.999 |
| III/IV | 9 (11.0) | 2 (11.1) | 7 (10.9) | ||
| CA (%) | I/II | 60 (73.2) | 9 (50.0) | 51 (79.7) | 0.027 |
| III/IV | 22 (26.8) | 9 (50.0) | 13 (20.3) | ||
| ECOG PS (%) | <2 | 59 (72.0) | 14 (77.8) | 45 (70.3) | 0.744 |
| ≥2 | 23 (28.0) | 4 (22.2) | 19 (29.7) | ||
| B symptom (%) | Absence | 48 (58.5) | 8 (44.4) | 40 (62.5) | 0.270 |
| Presence | 34 (41.5) | 10 (55.6) | 24 (37.5) | ||
| KPI (%) | LR | 25 (30.5) | 3 (16.7) | 22 (34.4) | 0.039 |
| LIR | 30 (36.6) | 4 (22.2) | 26 (40.6) | ||
| HIR | 19 (23.2) | 8 (44.4) | 11 (17.2) | ||
| HR | 8 (9.8) | 3 (16.7) | 5 (7.8) | ||
| NRI (%) | ILR | 16 (19.51) | 1 (5.56) | 15 (24.59) | 0.154 |
| IHR | 45 (54.88) | 14 (77.78) | 31 (48.44) | ||
| HR | 13 (15.85) | 2 (11.11) | 11 (17.19) | ||
| Very HR | 8 (9.76) | 1 (5.56) | 7 (10.94) | ||
| PINK (%) | LR | 29 (35.4) | 6 (33.3) | 23 (35.9) | 0.307 |
| IR | 32 (39.0) | 5 (27.8) | 27 (42.2) | ||
| HR | 21 (25.6) | 7 (38.9) | 14 (21.9) | ||
| IPI (%) | LR | 54 (65.9) | 12 (66.7) | 42 (65.6) | 0.856 |
| LIR | 18 (22.0) | 3 (16.7) | 15 (23.4) | ||
| HIR | 6 (7.3) | 2 (11.1) | 4 (6.2) | ||
| HR | 4 (4.9) | 1 (5.6) | 3 (4.7) | ||
| >240 | 34 (41.5) | 11 (61.1) | 23 (35.9) | ||
| EBER | Negative | 12 (14.63) | 3 (16.67) | 9 (14.06) | 0.782 |
| Positive | 70 (85.37) | 15 (83.33) | 55 (55.94) | ||
Note: CA: Chinese Southwest Oncology Group and Asia Lymphoma Study Group staging system; ECOG PS: Eastern Cooperative Oncology Group performance status; KPI: Korean Prognostic Index; NRI: the nomogram-revised risk index; PINK: Prognostic index of natural killer lymphoma; IPI: International Prognostic Index; LR: low risk; ILR: intermediate low risk; IHR: high risk; HR: intermediate high risk; LDH: serum lactate dehydrogenase.
Immunohistochemical characteristics of OX40 and ICOS
Positive staining for OX40 and ICOS was primarily localized in the membrane of tumor cells (Figure 1). Among these samples, 64 (78.0%) showed positive staining for OX40, and 48 (58.5%) showed positive staining for ICOS. Notably, 45 samples were found to be double positive.
Figure 1.
Representative histological (HE) and immunohistochemical staining of OX40 and ICOS in ENKTL. A: HE of OX40-positive; B: HE of OX40-negative; C: HE of ICOS-positive; D: HE of ICOS-negative; E: immunohistochemical staining of OX40-positive; F: immunohistochemical staining of OX40-negative; G: immunohistochemical staining of ICOS-positive; H: immunohistochemical staining of ICOS-negative; (original magnification, ×400 for all panels).
Clinicopathological characteristics of OX40 and ICOS
OX40-positive and OX40-negative groups differed mainly in CA stage (Table 1). ICOS-negative and ICOS-positive groups only differed in CD152 background cells (Supplementary Table 1).
Survival analysis of OX40 and ICOS
Patients exhibiting positive OX40 expression demonstrated a statistically significant improvement in OS compared to the negative group (p < 0.001, Figure 2(A)). In contrast, no statistically significant survival difference was observed between ICOS-negative and ICOS-positive patients (p = 0.760, Figure 2B). Additionally, when analyzing subgroups with mixed expressions, the OX40+/ICOS- subgroup, comprising 19 patients, showed better survival outcomes compared to the three patients in the ICOS+/OX40- subgroup. Upon combining the data for OX40 and ICOS expression, a notable enhancement in survival was observed in patients from the dual-positive group, when compared with both the dual-negative group (p = 0.004).
Figure 2.
Kaplan-Meier Survival curves of ENKTL patients. (A) OX40 status; (B) ICOS status.
Table 2 showed the results of the univariable analysis. After multiple iterations in the multivariable analysis, we found that advanced CA stage was an adverse prognostic factor (HR = 2.258, 95% CI: 1.004–5.077, p = 0.049). Conversely, the expression of OX40 was a favorable prognostic indicator for ENKTL patients (HR = 0.049, 95% CI: 0.009–0.285, p < 0.001).
Table 2.
Univariable analysis of prognostic factors for OS in ENKTL patients.
| Variables | HR | 95% CI | P | |
|---|---|---|---|---|
| Ann Arbor Stage | I/II | 1 | Ref | |
| III/IV | 2.672 | 1.093–6.531 | 0.031 | |
| CA Stage | I/II | 1 | Ref | |
| III/IV | 3.276 | 1.610–6.664 | 0.001 | |
| OX40 | Negative | 1 | Ref | |
| Positive | 0.236 | 0.115–0.484 | <0.001 | |
| OX40/ICOS | Dual negative | 1 | Ref | |
| Others | 0.262 | 0.095–0.724 | 0.010 | |
| Dual positive | 0.320 | 0.143–0.716 | 0.006 | |
Note: CA: Chinese Southwest Oncology Group and Asia Lymphoma Study Group staging system; ICOS: inducible T-cell co-stimulator.
Subgroup analysis of OX40 and ICOS expression with clinicopathological indexes
To explore the prognostic values of OX40 and ICOS expression in different clinicopathological indexes, a subgroup analysis was conducted. These findings revealed a significant correlation between CD152 and ICOS (r = 0.368, p = 0.012). OX40 expression could stratify the survival of patients in ECOG (<2), Ann Arbor stage, CA stage, PINK (IR/HR), CD38-positive, PD1, CD30, CD152-positive, P53-positive, and CD68-positive groups (Figure 3).
Figure 3.
Kaplan-Meier Survival curves of ENKTL patients. OX40 expression in (A) ECOG (<2) group; (B) Ann arbor stage (I/II) group; (C) Ann arbor stage (III/IV) group; (D) CA (I/II) group; (E) CA (III/IV) group; (F) KPI (HIR/HR) group; (G) IPI (LR/LIR) group; (H) PINK (IR) group; (I) PINK (HR) group; (J) LMP1-negative group; (K) CD38 tumor cells-positive group; (L) CD163-positive group; (M) CD68-positive group; (N) PD1 tumor cells-negative group; (O) PD1 background cells-negative group; (P) PD1background cells-positive group; (Q) P53-positive group; (R) CD152-positive group; (S) CD30-negative group; (T) CD30-positive group; LR: low risk; LIR: low intermediate risk; HIR: high intermediate risk; HR: high risk.
Discussion
In this study, we explored the clinicopathological characteristics and prognostic values of co-stimulatory molecules OX40 and ICOS in ENKTL, identifying a positive correlation between OX40 expression and overall survival. To the best of our knowledge, this is the first study to assess the associations of OX40 and ICOS with ENKTL.
The lymphoma microenvironment has emerged as an important factor, particularly in the era of immunotherapy and targeted treatments. Its influence extends beyond treatment efficacy to enabling the development of more precise, individualized treatments. In our study, OX40 was expressed in 78% of the cases, with 12 showing expression levels exceeding 30%. Moreover, our results indicated a positive association between OX40 expression and improved survival outcomes in patients with ENKTL. Ramser et al. [25] reported that a high density of OX40-positive immune cells in recurrent cancer biopsies was significantly associated with better survival rates. Additionally, a cross-sectional study involving 20 patients demonstrated a positive correlation between OX40 expression on CD4+/CD8+ T cells and progression-free survival [26]. Similarly, Lu et al. [18] observed that patients with DLBCL exhibiting high OX40 expression experienced significantly better clinical outcomes. Nevertheless, the prevalence and prognostic value of OX40 expression in ENKTL require further exploration.
There are several possible mechanisms that could explain the positive association between OX40 expression and improved survival. First, OX40 is primarily expressed on activated CD4+ and CD8+ T cells as well as Foxp3+ CD4+ regulatory T cells (Tregs) [27,28]. The ligand for OX40 is OX40L. By binding with OX40L, OX40 can initiate a series of signal transduction events in T cells, including the recruitment of TNF receptor-associated factors, and the activation of key kinases such as IkappaB Kinase α/β, and phosphoinositide 3-kinases [29–31]. These signaling pathways not only enhance the survival and proliferation capabilities of T cells but also improve their functional responsiveness to antigens presented within the tumor environment, leading to an intensified cytotoxic attack on tumor cells. Second, the interaction between OX40 and OX40L can also regulate the production of cytokines, including enhancing the production of IL-2 and IFN-γ, and reducing the production of IL-10 [32,33]. This cytokine modulation is crucial for orchestrating an effective immune response, as IL-2 and IFN-γ are pivotal in enhancing T cell effector functions, while reducing IL-10 helps diminish the immunosuppressive environment typically fostered by tumors. Furthermore, prior research indicates that OX40 signaling can promote the generation of long-lived memory T cells, thereby enhancing immune memory [34,35]. In addition, combined treatments involving OX40 agonists and other immunotherapies may potentiate anti-tumor responses and improve survival rates.
In this current study, we observed that among the 48 patients with positive ICOS expression, 65% (n = 31) cases exhibited a minimal expression level of 1%. Moreover, there was no statistically significant difference in survival rates between patients who were ICOS-negative and those who were ICOS-positive. This minimal expression might not be biologically significant enough to impact the OS of ENKTL. Besides, the sample size may be too small to detect survival differences. Further investigation, which includes a larger cohort of patients, or different thresholds for ICOS positivity to clarify the potential role of ICOS in ENKTL. Additionally, we observed a statistically significant difference in the proportion of CD152-positive background cells between the ICOS status groups. CD152 is an immune checkpoint molecule predominantly expressed on regulatory T cells and activated T cells, playing a key role in maintaining immune homeostasis. This finding may reflect subtle immunological differences in the tumor microenvironment associated with ICOS status, although its clinical significance in ENKTL requires further elucidation.
When examining the combined positive expression of OX40 and ICOS, a marked improvement in survival rates was observed in the group of patients dual expressing, compared to those without such expression. This correlation could be attributed to several potential reasons. ICOS and OX40 are both co-stimulatory molecules on the surface of T cells, and their expression can lead to increased T cell activation and proliferation [36,37]. Their expression is associated with the formation of long-term immune memory [38,39], which could help the immune system in effectively responding to tumor growth. Furthermore, these molecules may modify the tumor microenvironment, making it more conducive to immune cell infiltration and function [40–42].
The strengths of our study include its long-term follow-up and the first-time investigation of the clinicopathological differences of ICOS and OX40 in ENKTL. Additionally, we conducted a detailed subgroup analysis of ICOS and OX40 status across various clinical pathological indicators. However, limitations of the current study are worth noting. First, we were unable to identify the cut-off points for OX40 and ICOS expression, which may affect the generalizability of the prognostic thresholds. Second, although our findings indicated that positive OX40 expression was a favorable prognostic factor in ENKTL, the limited sample size necessitates further large-scale, multicenter studies to explore the prognostic values of ICOS and OX40 in ENKTL more comprehensively. Lastly, the variation in treatment regimens across the study period was not stratified in this analysis, which could potentially influence the prognostic implications of OX40 and ICOS expression. Future research should incorporate these variables to more accurately elucidate how treatment strategies interact with biomarker performance and influence patient outcomes.
In conclusion, positive OX40 expression could serve as an independent prognostic marker for improved survival of ENKTL. While further studies are needed to clarify the impact of ICOS in ENKTL.
Supplementary Material
Funding Statement
This study was funded by National Natural Science Foundation of China (82470192), the Natural Science Foundation of Jiangsu Province (BK20171181), Jiangsu Key Research and Development Project of Social Development (BE2019638), Young Medical Talents of Jiangsu Science and Education Health Project (QNRC2016791), and Jiangsu Province High-Level Hospital Construction Project (GSPJS202417, GSPJS202420, GSPJS202414).
Author contributions
ZS, HL, and WS contributed to the concept and design; ZS and HZ contributed to the methods and analysis. HZ and YL contributed to the drafting. QZ, YW, SZ, and XX contributed to data collection. All authors approve the final version.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Ethical approval
The study was approved by the Ethics Committee of the Affiliated Hospital of Xuzhou Medical University (No. XYFY2022-KL363-01). All participants provided written informed consent.
Data availability statement
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.