Blood MALT1 serves as a potential biomarker reflecting the response and survival of immune‑checkpoint‑inhibitor therapy in advanced hepatocellular carcinoma
- Authors:
- Published online on: August 5, 2024 https://doi.org/10.3892/ol.2024.14609
- Article Number: 476
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Copyright: © Ma et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Hepatocellular carcinoma (HCC) ranks sixth in cancer morbidity and fourth in cancer-related mortality globally. It is a global disease burden, especially in Asia, where it accounts for ~72% of HCC cases (1,2). Owing to the late presentation of symptoms, >50% of patients with HCC are diagnosed at an advanced stage (3). Aside from the traditional molecular classification, HCC has recently begun to be classified according to the immunological environment, including active immune phenotypes (with enriched T cell response effectors), exhausted immune phenotypes [featured by T cell exhaustion, immunosuppressive macrophages and transforming growth factor β (TGFβ) signaling], and excluded immune phenotypes (immunosuppressive signatures in the surrounding tissues of the tumor but with little immune gene expression in the tumor core) (4). Moreover, the aforementioned immunological classification of advanced HCC is associated with different survival rates, which attracts the attention of clinicians to HCC immunity (5).
Mucosa-associated lymphoid tissue 1 (MALT1) is an intracellular signaling gene with both protease activity and scaffold function. It facilitates tumorigenesis by modulating cancer cell proliferation, migration and stemness in several solid cancers (6–10). A previous study reported that MALT1 serves as an oncogene by enhancing tumor cell proliferation and invasion in prostate carcinoma (8), and another study demonstrated that the MALT1 gene potentiates the crosstalk between TGFβ and nuclear factor κB (NF-κB) to participate in tumor progression (10). Notably, one study reported that MALT1 paracaspase was upregulated and facilitated cancer growth in an HCC cell line (9).
In addition to the direct oncogenic role, MALT1 also activates NF-κB signaling to regulate cytotoxic T lymphocytes and immune escape (9,11,12). For instance, a previous study reported that MALT1 restrained antitumor immunity by facilitating cluster of differentiation (CD)8+ T cell exhaustion (9). Another study reported that MALT1 decreased the activity of tumor-infiltrating CD8+ T cells and elevated the immunosuppressive effects of regulatory T cells (Tregs) in malignant melanoma (11). Notably, a previous study reported that MALT1 induced adaptive immune resistance and thereby weakened the response of tumor cells to immune-checkpoint inhibitor (ICI) treatment (12). Furthermore, the ICI-involved systemic treatment modality emerges with the evolving therapeutic landscape of advanced HCC and brings certain survival benefits (13,14). For instance, a phase III clinical trial (KEYNOTE-240) found that pembrolizumab following sorafenib plus best supportive care prolonged the survival of patients with advanced HCC compared to those with placebo plus best supportive care [hazard ratio (HR)=0.781, P=0.0238] (15). Another study showed that atezolizumab plus bevacizumab resulted in a better progression-free survival (PFS) compared to sorafenib in patients with unresectable HCC (median PFS, 6.8 vs. 4.3 months) (16). However, the ICI efficacy is varied among each patient with advanced HCC and, the treatment response of ICI is still unmet in certain patients (17).
Therefore, the present study aimed to assess the clinical significance of MALT1 for estimating ICI treatment outcomes in patients with advanced HCC, which, to the best of our knowledge, has not been reported yet.
Materials and methods
Subjects
A total of 51 patients with advanced HCC who were treated with an ICI or ICI-based therapy in Handan Central Hospital (Handan, China) between February 2020 and November 2022 were consecutively enrolled in the present study. The inclusion criteria were as follows: i) Diagnosis with primary HCC using a pathological method; ii) Barcelona Clinic Liver Cancer stage C (18) [also recognized as China liver cancer staging (CNLC) stage III (19)]; iii) age ≥18 years old; iv) Eastern Cooperative Oncology Group Performance Status (ECOG PS) score ≤2 (20); v) Child-Pugh stage A or B (21); and vi) scheduled to receive ICI or ICI-based treatment. The exclusion criteria were as follows: i) Additional malignant diseases; ii) absence of measurable lesion to be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (22); iii) refusal to provide peripheral blood (PB) sample for use in the present study; and iv) pregnancy or lactation. Furthermore, 50 healthy participants were enrolled as healthy controls (HCs), whose eligibility criteria were as follows: i) No signs of abnormalities in recent physical examinations; ii) age and sex-matched with patients with advanced HCC; and iii) willingness to cooperate with this study. The Ethics Committee of Handan Central Hospital approved the present study and all subjects gave their written informed consent to participate.
Data and samples
Clinical characteristics were collected from patients with advanced HCC, including demographics and disease-related characteristics. PB samples were obtained from patients with advanced HCC before treatment initiation, whilst samples from HCs were obtained at enrollment.
After PB sample collection, PB mononuclear cells (PBMCs) were isolated using the Ficoll-Paque® centrifugation machine (GE Healthcare). Subsequently, the levels of MALT1 in PBMCs were detected using reverse transcription (RT)-quantitative (q)PCR. The RNeasy® Protect Mini Kit (Qiagen GmbH) was used for total RNA extraction, and then the PrimeScript™ RT Reagent Kit (Takara Biotechnology Co., Ltd.) was used for RT (37°C for 15 min, 85°C for 5 sec). Subsequently, qPCR (1 cycle of 95°C for 30 sec, 40 cycles of 95°C for 5 sec and 60°C for 10 sec) was performed using the TB Green® Fast qPCR Mix (Takara Biotechnology Co., Ltd.). GAPDH was set as an internal reference. The quantitation of MALT1 was calculated using the 2−ΔΔCq method (23). The sequences of primer for MALT1 and GAPDH were the same as in a previous study (24).
Treatment regimen
The present study was an observational study and the authors did not intervene in the treatment of the enrolled patients. ICI monotherapy or ICI-based treatments were administered according to the disease status of the patients, physician consultations and willingness of the patients to undergo the treatments. The regimens included: i) Camrelizumab + apatinib (25); ii) pembrolizumab + lenvatinib (26); iii) sintilimab + lenvatinib (27); iv) atezolizumab + bevacizumab (28); v) sintilimab monotherapy (29); vi) camrelizumab monotherapy (30); vii) atezolizumab monotherapy (31); and viii) nivolumab monotherapy (32). In detail, the dosage was as follows: 200 mg camrelizumab was administered intravenously every 2 weeks; 250 mg apatinib was given orally on day 1 of a 21-day cycle; 200 mg pembrolizumab was administered intravenously on day 1 of a 21-day cycle; 8 mg lenvatinib for bodyweight <60 kg and 12 mg for bodyweight ≥60 kg was administered orally once daily; 200 mg sintilimab was given intravenously on day 1 of a 21-day cycle; 1,200 mg atezolizumab was administered intravenously on day 1 of a 21-day cycle; 15 mg/kg bevacizumab was given intravenously on day 1 over a 21-day cycle; and 3 mg/kg nivolumab was administered intravenously every 2 weeks. The drug treatment was continued until disease progression, intolerable toxicity or voluntarily withdrawal from the treatment.
Follow-up and evaluation
Patients with advanced HCC underwent routine follow-ups, with a median follow-up of 13.3 months (range, 1.4–29.4 months). The last follow-up was performed in March 2023. During the follow-up, patients received imaging examinations every 2 cycles (~42 days). Based on treatment response data after 4 cycles (~3 months), the objective response rate (ORR) and disease control rate (DCR) were calculated, which was assessed according to RECIST version 1.1 (33). The ORR was defined as the sum of complete response (CR) and partial response (PR) rates, whereas the DCR was defined as the sum of CR, PR and stable disease (SD) rates. In addition, the PFS and overall survival (OS) were calculated according to the disease status or death of a patient.
Statistical analysis
SPSS 26.0 (IBM Corp.) and GraphPad Prism 7.01 (Dotmatics) were used for analyzing data and plotting figures, respectively. The Wilcoxon rank-sum test was used for comparison analysis and the Spearman's rank correlation coefficient test was used for correlation analysis. The receiver operating characteristics curve demonstrated the ability of MALT1 to differentiate patients with advanced HCC from HCs. To estimate the effect of MALT1 on prognosis in patients with advanced HCC, MALT1 was divided into high and low levels by its median value. The Kaplan-Meier curve was used to assess the PFS and OS, in which the log-rank test was used for comparing PFS and OS between patients with high and low MALT1. Univariate and multivariate Cox regression models were used to identify factors associated with PFS and OS, in which the forward stepwise method was performed in the multivariate model. All factors included in the univariate model were put into the forward stepwise-multivariate model. P<0.05 was considered to indicate a statistically significant difference.
Results
Characteristics of patients with advanced HCC
Among the 51 patients with advanced HCC, there were 7 (13.7%) females and 44 (86.3%) males, whose mean age was 59.0±8.3 years. A total of 13 (25.5%), 36 (70.6%) and 2 (3.9%) patients had ECOG PS scores of 0, 1, and 2, respectively. Moreover, 44 (86.3%), 21 (41.2%) and 32 (62.7%) patients had portal vein invasion, hepatic vein invasion and extrahepatic disease, respectively. A total of 19 (37.3%) and 32 (62.7%) patients were diagnosed as CNLC stage IIIa and IIIb, respectively. Detailed information regarding the patients is presented in Table I.
Treatment information of patients with advanced HCC
A total of 19 (37.3%) patients received ICI therapy as a first-line treatment, whilst 32 (62.7%) patients were treated with ICI therapy as a second-line treatment. Furthermore, 11 (21.6%), 5 (9.8%), 5 (9.8%), 4 (7.8%), 9 (17.6%), 8 (15.7%), 6 (11.8%) and 3 (5.9%) patients received camrelizumab + apatinib, pembrolizumab + lenvatinib, sintilimab + lenvatinib, atezolizumab + bevacizumab, sintilimab monotherapy, camrelizumab monotherapy, atezolizumab monotherapy and nivolumab monotherapy, respectively (Table II).
Blood MALT1 levels in patients with advanced HCC and HCs
Blood MALT1 levels were significantly increased in patients with advanced HCC compared with HCs (P<0.001; Fig. 1A) and it possessed a good ability to distinguish patients with advanced HCC from HCs (area under the curve, 0.895; 95% confidence interval, 0.836–0.954; Fig. 1B).
Relationship between blood MALT1 levels and tumor features in patients with advanced HCC
Blood MALT1 levels were significantly increased in patients with portal vein invasion (vs. without portal vein invasion; P=0.010), extrahepatic disease (vs. without extrahepatic disease; P=0.026) and α-fetoprotein (AFP) ≥200 ng/ml (vs. AFP <200 ng/ml; P=0.040). However, blood MALT1 levels were not significantly correlated with ECOG PS score (r=0.193, P=0.175) or significantly varied in patients with Child-Pugh stage A (vs. stage B; P=0.145), largest tumor size >10 cm (vs. ≤10 cm; P=0.053), hepatic vein invasion (vs. without; P=0.157) or programmed cell death 1 ligand 1 combined positive score (PD-L1 CPS) ≥1 (vs. PD-L1 CPS<1; P=0.095) (Table III).
 | Table III.Relationship between mucosa-associated lymphoid tissue 1 in patients with advanced hepatocellular carcinoma and different tumor features. |
Association between blood MALT1 levels and clinical response in patients with advanced HCC who received ICI therapy
After 4 cycles of ICI therapy, 0 (0.0%), 15 (29.4%), 20 (39.2%) and 16 (31.4%) patients with advanced HCC had CR, PR, SD and progressive disease, respectively; thus, the ORR and DCR were 29.4 and 68.6%, respectively (Fig. 2A). Notably, blood MALT1 levels were significantly decreased in patients with ORR (vs. without ORR; P=0.043; Fig. 2B) and DCR (vs. without DCR; P=0.004) (Fig. 2C).
Association between blood MALT1 levels and PFS and OS in patients with advanced HCC who received ICI therapy
Accumulating PFS was shortened in patients with high blood MALT1 levels compared to those with low blood MALT1 levels (P=0.008). Specifically, the 6-, 12-18- and 24-month accumulating PFS rates in patients with high blood MALT1 levels were 50.0, 20.8, 8.3 and 0.0%, respectively, whereas they were 63.5, 44.8, 30.7 and 0.0% in patients with low blood MALT1 levels (Fig. 3A).
Moreover, accumulating OS was shortened in patients with high blood MALT1 levels in comparison with those with low blood MALT1 levels (P=0.040). Specifically, the 6-, 12-, 18-, 24- and 30-month cumulative OS rates were 84.4, 55.3, 28.7, 17.2 and 17.2% in patients with high blood MALT1 levels, respectively, whereas the rates at the aforementioned time points were 100.0, 86.1, 61.1, 29.1 and 29.1% in patients with low blood MALT1 levels, respectively (Fig. 3B).
Risk factors associated with a shorter PFS in patients with advanced HCC who received ICI therapy
High blood MALT1 levels (P=0.011), age ≥60 years (P=0.006), higher ECOG PS score (P=0.011), Child-Pugh stage B (vs. A) (P=0.038), largest tumor size >10 cm (P=0.021), portal vein invasion (P=0.024), extrahepatic disease (P=0.006), AFP ≥200 ng/ml (P=0.020), treatment line of 2 (vs. 1; P=0.029), sintilimab monotherapy (vs. camrelizumab + apatinib; P=0.035), and camrelizumab monotherapy (vs. camrelizumab + apatinib; P=0.013) were significantly associated with a shorter PFS; however, PD-L1 CPS ≥1 (P=0.004) was significantly associated with a longer PFS in patients with advanced HCC who received ICI therapy (Fig. 4A). After adjustment, high blood MALT1 levels [HR=2.419; P=0.009], higher ECOG PS score (HR=2.925; P=0.007) and treatment line of 2 (vs. 1; HR=2.213; P=0.036) were independent factors significantly associated with a shorter PFS in patients with advanced HCC who received ICI therapy (Fig. 4B).
Risk factors associated with a shorter OS in patients with advanced HCC who received ICI therapy
High blood MALT1 levels (P=0.046), higher ECOG PS score (P=0.031), largest tumor size >10 cm (P=0.004), extrahepatic disease (P=0.022), AFP ≥200 ng/ml (P=0.001), treatment line of 2 (vs. 1; P=0.002), sintilimab monotherapy (vs. camrelizumab + apatinib; P=0.002) and camrelizumab monotherapy (vs. camrelizumab + apatinib; P=0.014) were significantly associated with a shortened OS; however, PD-L1 CPS ≥1 (P=0.020) was significantly associated with a longer OS in patients with advanced HCC who received ICI therapy (Fig. 5A). Furthermore, high blood MALT1 levels (HR=2.706; P=0.018), higher ECOG PS score (HR=4.642; P=0.004), largest tumor size >10 cm (HR=4.114; P=0.002) and treatment line of 2 (vs. 1; HR=11.521; P<0.001) were independently significantly associated with a shorter OS in patients with advanced HCC who received ICI therapy (Fig. 5B).
Discussion
Although the oncogenic role of MALT1 is well-elucidated, only two previous studies have investigated MALT1 in HCC, to the best of our knowledge (34,35). For instance, one of the aforementioned studies reported that MALT1 inhibited HCC cell apoptosis and facilitated HCC progression through competitively binding to tumor necrosis factor receptor-associated factor (TRAF)6 with TRAF-interacting protein with Forkhead-associated domain (34). The other study reported that MALT1 was elevated and promoted migration, invasion and tumor-forming ability in human HCC cell lines (35). The aforementioned studies provide evidence of molecular implications of MALT1 in HCC, whereas the clinical role of blood MALT1 in patients with advanced HCC remains unclear.
The present study demonstrated that blood MALT1 levels were elevated in patients with advanced HCC compared with HCs, and increased blood MALT1 levels was associated with portal vein invasion, extrahepatic disease and AFP ≥200 ng/ml in patients with advanced HCC. A possible explanation could be as follows: i) MALT1 is a well-known oncogene, whose elevation promoted tumor development (6,7). Consequently, blood MALT1 levels were elevated in patients with advanced HCC compared with that in HCs; and ii) MALT1 has been reported to promote migration and invasion in an HCC cell line (35). As a result, blood MALT1 levels were positively associated with portal vein invasion and extrahepatic disease in patients with advanced HCC.
AFP, identified 60 years ago, is the most widely used serum biomarker to detect HCC and predict the prognosis (36). The results of the present study demonstrated that elevated blood MALT1 levels were associated with AFP ≥200 ng/ml in patients with advanced HCC, which may be explained as follows: MALT1 aggravated the progression of HCC which is typically reflected by elevated AFP (37). Consequently, elevated blood MALT1 levels was associated with AFP ≥200 ng/ml in patients with advanced HCC. As AFP is a well-known marker of HCC, this finding of the present study further provides evidence supporting the clinical utilization of MALT1 in patients with advanced HCC.
Furthermore, MALT1 has recently gained additional attention due to its role in regulating the immunological environment (9,11,38,39). For example, a previous study reported that MALT1 paracaspase activity mediated the T cell receptor-induced NF-κB activation in Tregs, which induced the conversion of resting Tregs into effector Tregs, thus facilitating the immune escape of tumor cells. Conversely, inhibiting MALT1 paracaspase activity could enhance antitumor immunity (11). Another study reported that MALT1 self-cleavage promoted interleukin-2 expression in conventional CD4+ T cells to regulate Treg homeostasis. Moreover, inhibition of MALT1 self-cleavage can cause Treg deficit, which enhances the antitumor immune reactivity (40). Based on the aforementioned results, a bioinformatic analysis identified that MALT1 could eliminate the antitumor effect of ICI by impairing the activation of CD8+ T cells (39). Notably, the density of liver-infiltrated Treg cells is increased in HCC and associated with the suppression of antitumor immunity, meanwhile, exhausted CD8+ T cells are the landmark of the HCC tumor microenvironment (41–43). Therefore, the regulatory role of MALT1 on Treg cells and CD8+ T cells suggests its involvement in antitumor immunotherapy of HCC. In the current study, it was demonstrated that blood MALT1 levels were negatively associated with ORR and DCR in patients with advanced HCC who received ICI therapy. The possible reasons are as follows: i) MALT1 attenuated the immune surveillance function of CD8+ T cells and promoted Treg cell-mediated immune escape, which further restrained the treatment response of ICI therapy (12,44,45); and ii) MALT1 activated dendritic cells to regulate immunosuppressive factors, thus the immunotherapy resistance of HCC cells was facilitated (46). Blood MALT1 levels were therefore negatively associated with a reduced ORR and DCR after ICI therapy in patients with advanced HCC.
Apart from treatment response, the present study also demonstrated that high blood MALT1 levels were an independent risk factor for a shortened PFS and OS in patients with advanced HCC who received ICI therapy. The possible explanations are as follows: i) MALT1, together with B-cell lymphoma/leukemia 10 (BCL10) and caspase recruitment domain family member (CARD) to form the CARD-BCL10-MALT1 (CBM) complex, promoted tumor progression and resulted in a worse survival in patients with advanced HCC (47); and ii) MALT1 restrained the treatment response towards ICI; thus, the survival benefits of ICI therapy were impaired in patients with advanced HCC. Therefore, high blood MALT1 levels were independently associated with a shortened PFS and OS in patients with advanced HCC who received ICI therapy.
However, the present study had the following limitations: i) Considering that ICI treatment was only recently used in advanced HCC, the present study could only enroll 51 eligible patients, and the small sample size weakened the statistical power; ii) the mean age of the enrolled patients was 59.0±8.3 years, whilst the prognostic value of blood MALT1 levels in elderly patients with HCC (generally defined as age ≥65 years) remained unknown; and iii) MALT1 may have formed a CBM complex to exert a biological regulatory effect; however, the other two components of the CBM complex (BCL10 and CARD) were not detected in the present study, which warrants further investigations; and iv) the change of blood MALT1 during treatment was not evaluated and its association with treatment response and survival should be explored in the future.
In summary, high blood MALT1 levels reflect a worse ICI-treatment response and survival in patients with advanced HCC, and therefore, this may be a potential target to improve ICI treatment outcomes in patients with advanced HCC that warrants further exploration.
Acknowledgements
Not applicable.
Funding
This study was supported by the Science and Technology Research and Development Project of Handan (grant no. 23422083200).
Availability of data and materials
The datasets generated in the present study may be requested from the corresponding author.
Authors' contributions
WM and LT designed the study and analyzed the data. YY and BD collected the data and reviewed the relevant literature. WM, YY, BD and LT wrote the original draft. LW reviewed the relevant literature, analysed the data, prepared the tables and figures, and revised the manuscript. WM and LT confirm the authenticity of all the raw data. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The Ethics Committee of Handan Central Hospital (Handan, China) approved the present study, and all subjects provided written informed consent.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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