MYELOID-DERIVED SUPPRESSOR CELLS TWO YEARS AFTER HEPATITIS C VIRUS ERADICATION USING DIRECTLY ACTING ANTIVIRALS

Células supressoras mieloides derivadas dois anos após a erradicação do vírus da hepatite C usando antivirais de ação direta

ABSTRACT

Background:

Myeloid-derived suppressor cells (MDSCs) have immature morphology, relatively weak phagocytic activity, as well as some immunosuppressive functions. The capacity of MDSCs to inhibit T-cell-mediated immunological responses is their most notable functional characteristic. Down-regulating antitumor immune surveillance is one way that the expansion and activation of MDSCs contribute significantly to the occurrence and progression of tumors. Increased levels of MDSCs in patients with chronic hepatitis C virus (HCV) infection could suppress T-cell responses, promoting viral escape and hepatitis progression. This may make HCV-infected individuals more vulnerable to severe infections, hepatic and extra-hepatic tumors, and a diminished capacity to react to immunization. It is still unknown if effective HCV eradication with directly acting antivirals (DAAs) can restore immune functions and immune surveillance capacity.

Objective:

The purpose of this study was to observe the frequency of M-MDSCs (CD33+, CD11b+, and HLA-DR) in patients with a previous history of HCV, 2-3 years after virus eradication using DAA therapy.

Methods:

This study was conducted on 110 subjects: fifty-five subjects without liver cirrhosis who were treated with HCV using DAAs and attained SVR for a period of 2-3 years and 55 age- and gender-matched healthy controls. The study was conducted during the period from January to July 2022. Patients were recruited from the National Viral Hepatitis Treatment Unit, Alexandria University Hepatology outpatient clinic, and the Alexandria University Tropical Medicine outpatient clinic. The frequencies of MDSCs (CD33+CD11b + HLA-DR-) by flow cytometry were assessed.

Results:

Even after the virus had been eradicated for longer than two years, MDSC levels in HCV-treated individuals were found to be considerably higher. In the HCV-treated group, the median number of MDSCs was 5, with an interquartile range (IQR) of 3.79-7.69. In contrast, the median for the control group was 3.1, with an IQR of 1.4-3.2 (P˂0.001).

Conclusion:

Successful DAA therapy leads to slow and partial immunological reconstitution, as demonstrated by the failure to attain normal levels of MDSC’s 2 years after successful HCV eradication despite the normalization of laboratory parameters as well as the absence of liver fibrosis. The clinical implications of these findings should be thoroughly studied.

Keywords:
Hepatitis C; viral hepatitis; liver; myeloid-derived suppressor cells; direct-acting antivirals

RESUMO

Contexto:

As células supressoras derivadas de mieloides (CSDMs) possuem morfologia imatura, atividade fagocítica relativamente fraca e algumas funções imunossupressoras. A capacidade das CSDMs de inibir respostas imunológicas mediadas por células T é sua característica funcional mais notável. A expansão e ativação das CSDMs contribuem significativamente para a ocorrência e progressão de tumores, regulando negativamente a vigilância imunológica antitumoral. Níveis aumentados de CSDMs em pacientes com infecção crônica pelo vírus da hepatite C (HCV) poderiam suprimir respostas das células T, promovendo a fuga viral e a progressão da hepatite. Isso pode tornar os indivíduos infectados pelo HCV mais vulneráveis a infecções graves, tumores hepáticos e extra-hepáticos, e a uma capacidade diminuída de reagir à imunização. Ainda não se sabe se a erradicação eficaz do HCV com antivirais de ação direta (AAD) pode restaurar as funções imunológicas e a capacidade de vigilância imunológica.

Objetivo:

O objetivo deste estudo foi observar a frequência de M-CSDMs (CD33+, CD11b+ e HLA-DR-) em pacientes com histórico anterior de HCV, 2-3 anos após a erradicação do vírus usando terapia com AADs.

Métodos:

Este estudo foi realizado em 110 indivíduos: 55 indivíduos sem cirrose hepática que foram tratados com AADs para HCV e atingiram resposta virológica sustentada (SVR) por um período de 2-3 anos e 55 controles saudáveis pareados por idade e gênero. O estudo foi conduzido no período de janeiro a julho de 2022. Os pacientes foram recrutados da Unidade Nacional de Tratamento de Hepatites Virais, da clínica ambulatorial de Hepatologia da Universidade de Alexandria e da clínica ambulatorial de Medicina Tropical da Universidade de Alexandria. As frequências de CSDMs (CD33+CD11b+HLA-DR-) foram avaliadas por citometria de fluxo.

Resultados:

Mesmo após a erradicação do vírus por mais de dois anos, os níveis de CSDMs em indivíduos tratados para HCV foram consideravelmente mais altos. No grupo tratado para HCV, o número mediano de CSDMs foi de 5, com um intervalo interquartil (IQR) de 3,79-7,69. Em contraste, a mediana para o grupo controle foi de 3,1, com um IQR de 1,4-3,2 (P<0,001).

Conclusão:

A terapia bem-sucedida com AADs leva a uma reconstituição imunológica lenta e parcial, como demonstrado pela falha em atingir níveis normais de CSDMs 2 anos após a erradicação bem-sucedida do HCV, apesar da normalização dos parâmetros laboratoriais e da ausência de fibrose hepática. As implicações clínicas desses achados devem ser estudadas minuciosamente.

Palavras-chave:
Hepatite C; hepatite viral; fígado; células supressoras derivadas de mieloides; antivirais de ação direta

HIGHLIGHTS

•We aimed to determine if the levels of myeloid-derived suppressor cells (MDSCs) return to normal 2-3 years after the eradication of the hepatitis C virus.

•We enrolled 110 subjects, 55 HCV-treated subjects with sustained virologic response for 2-3 years, and 55 healthy controls.

•Levels of MDSCs were significantly higher among previously treated HCV patients than in the control group.

•Levels of MDSCs do not return to normal among HCV patients, even 2-3 years after successful HCV eradication, and the clinical impacts of this finding should be further investigated.

INTRODUCTION

Myeloid-derived suppressor cells (MDSCs) are a diverse group of immature myeloid cells that are produced from hematopoietic stem cells (HSCs) because of altered myelopoiesis¹. Immature myeloid cells (IMCs) make up approximately 0.5% of peripheral blood mononuclear cells in healthy individuals². MDSCs accumulate in the blood and lymphoid organs in cases of chronic inflammation, sepsis, severe burn injuries, autoimmune diseases, and malignancies³.

In cases of acute infections, myeloid cells quickly migrate out of the bone marrow (BM) and become physiologically activated in response to pathogenic signals like toll-like receptor (TLR) ligands, damage-associated molecular patterns (DAMPs), and pathogen-associated molecular patterns (PAMPs). This leads to a significant rise in phagocytosis and the up-regulation of pro-inflammatory cytokines⁴. Once the stimulus is removed, this brief myelopoiesis ends, and the myeloid cells’ homeostasis returns⁴. However, in chronic infections, persistent inflammation signals lead to the accumulation of MDSCs^5-7. These MDSCs have immature morphology, relatively weak phagocytic activity, as well as some immunosuppressive functions⁶. The capacity of MDSCs to inhibit T-cell-mediated immunological responses is their most notable functional characteristic^3,8.

It is challenging to identify a single phenotypic profile that typifies all of the diverse cell types that may fall under this category. A consensus has been reached by using markers that unambiguously show their myeloid origin, such as Gr-1 and Cd11b (Mac-1) in rodents and CD33 and CD11b (as well as negative for lymphoid, NK, monocytic, and DC markers) in human MDSC⁹.

According to recent research, down-regulating antitumor immune surveillance is one way that chronic inflammation and the expansion and activation of MDSCs contribute significantly to the occurrence and progression of tumors¹⁰.

Increased levels of MDSCs in patients with chronic hepatitis C virus (HCV) infection could suppress T-cell responses, promoting viral escape and hepatitis progression¹¹. It has been noted that the monocytic MDSCs (M-MDSCs) among the various subsets of MDSCs accumulate more during HCV infection¹¹. These immune dysfunctions may make HCV-infected individuals more vulnerable to severe infections¹², hepatic and extra-hepatic tumors¹², and a diminished capacity to react to immunization¹³.

In HCV-cured patients, it is still unknown if effective HCV eradication with directly acting antivirals (DAAs) can restore immune functions and immune surveillance capacity^13,14.

The purpose of this study was to observe the frequency of M-MDSCs (CD33+, CD11b+, and HLA-DR) in patients with a previous history of HCV, 2-3 years after virus eradication using DAA therapy.

METHODS

This study was conducted on 110 subjects: 55 subjects without liver cirrhosis who were treated with HCV using DAAs and attained SVR for a period of 2-3 years and 55 age- and gender-matched healthy controls. The study was conducted during the period from January to July 2022. Patients were recruited from the National Viral Hepatitis Treatment Unit, Alexandria University Hepatology outpatient clinic, and the Alexandria University Tropical Medicine outpatient clinic. All subjects were asked to freely volunteer for the study, and informed written consent was gathered before their inclusion in the study protocol. This study had been approved by the Ethics Committee of the Faculty of Medicine, Alexandria University (IRB no. 00012098, FWA no. 00018699) and given serial number 0107127. All study procedures were subject to the Declaration of Helsinki.

The study included fifty-five patients with a previous history of HCV infection as evidenced by positive PCR who received successful treatment with combined sofosbuvir 400 mg and daclatasvir 60 mg once daily for twelve weeks according to the National Egyptian guidelines for genotype 4 treatment¹⁵, with successful HCV eradication evidenced by a sustained virological response (SVR) 12 weeks following cessation of treatment. Treatment cessation was 2-3 years before inclusion in the study. All patients in this study were subjected to a clinical examination to exclude any signs of liver cirrhosis. FIB-4 and Fibroscan were used to exclude the presence of advanced fibrosis¹⁶. Patients with a current or previous history of malignancy or autoimmune diseases, pregnant patients, and HBV- or HIV-co-infected patients were excluded from the study.

A thorough history, including type of HCV treatment, duration since SVR, and associated comorbidities, was obtained from all subjects. A complete clinical examination was done for all patients. Serum samples were obtained for ALT, AST, bilirubin, urea, creatinine, and AFP measurements. Venous samples were collected for a complete blood count (CBC), including a differential leukocytic count as well as an international normalized ratio (INR) measurement. Ultrasonography of the abdomen and pelvis and a fibroscan to measure liver stiffness were performed for all participants.

Two mL of blood were collected from each participant in sterile containers coated with ethylenediamine tetraacetic acid (EDTA) to determine the frequencies of MDSCs (CD33+CD11b + HLA-DR-) by flow cytometry. The PBMCs were separated. Then, Fluorescein isothiocyanate (FITC) Mouse Anti-Human CD33 from BD Bioscience Pharmingen TM, San Diego, USA (Clone HIM3‐4, Cat 555626/Lot 0023203), Phycoerythrin (PE) Mouse Anti-Human CD11b/Mac-1 from BD Bioscience Pharmingen TM, San Diego, USA (Clone ICRF44, Cat 555388/Lot 9204345), PerCP Anti-HLA-DR (L243) from BD Biosciences, San Jose, CA, USA, BD FACS TM Lysing Solution from BD Biosciences, San Jose, CA, USA (Cat 349202), and phosphate-buffered saline PBS (0,0067M) were used to detect MDSCs. In 15 mL polystyrene BD Falcon TM tubes, 100 μL of resuspended PBMCs (100.000 cells) were added, and then the cells were treated with 2 µL of PE (CD11b) and 2 µL of FITC (CD33). After that, they were gently mixed with a vortex mixer. After adding 1 µL of L243 (anti-HLA-DR) monoclonal antibodies, the mixture was softly mixed using a vortex mixer. Anti-coagulated whole blood devoid of conjugated antibodies was utilized as a negative control. For 30 minutes, the tubes were incubated at room temperature (20-25°C) in the dark. Then the tubes were centrifuged for five minutes at 1800 rpm at room temperature following incubation. After discarding the supernatant, the cells were centrifuged twice with 2 mL of PBS per wash for five minutes at 1800 rpm at room temperature. The supernatant was then decanted. To achieve a uniform cell distribution, the pellets were again suspended in 2 mL of PBS and very gently stirred using a vortex mixer. Finally, all tubes were analyzed by flow cytometry. The resulting information was displayed in two dimensional dot-plot formats reflecting right-angle light scatter or side scatter (SSC) versus forward-angle light scatter (FSC). A gate was drawn for each HLA-DR- lymphocyte; the fluorescence attributable to the PE conjugate and FITC monoclonal antibodies was collected, and the percentage was determined. Figure 1 shows a dot-plot graph representing SSC on the Y-axis versus FSC on the X-axis, then gated on granulocytes to exclude monocytes, lymphocytes, debris, and dead cells. Figure 2 shows a dot-plot graph representing only the previously gated cells, with the lower quadrant R2 showing negative HLA-DR cells on the X-axis as a marker for MDSCs. Figure 3 shows a dot-plot graph representing only the previously gated cells of the second graph, divided into 4 quadrants with CD11b-PE on the Y-axis and CD33-FITC on the Xaxis as markers for MDSC. The upper right quadrant cells were gated, showing (CD33+ CD11b+ HLA-DR-) representing the MDSC frequency.

FIGURE 1
Flow cytometer gating analysis for the granulocytes. A dot-plot graph representing side scatter (SSC) on the Y-axis versus forward scatter (FSC) on the X-axis. A gate was applied to granulocytes to exclude monocytes, lymphocytes, debris, and dead cells.

FIGURE 2
Flow cytometer gating analysis for the low or negative HLADR. A dot-plot graph representing only the previously gated cells. The lower quadrant R2 shows negative HLA-DR cells on the X-axis.

FIGURE 3
Flow cytometer gating analysis for the CD11b+ CD33+ to identify myeloid-derived suppressor cells (MDSCs). A dot-plot graph representing only the previously gated cells of the second graph, divided into four quadrants with CD11b-PE on the Y-axis and CD33-FITC on the X-axis as markers for MDSCs. The upper right quadrant cells were gated, showing (CD33+ CD11b+ HLA-DR-) representing the MDSC frequency.

Statistical analysis

IBM SPSS version 20.0 (Armonk, NY: IBM Corp.) was used for data analysis. Categorical data were represented as numbers and percentages. The two groups were compared using the chi-square test. The Kolmogorov-Smirnov test was used to check for normalcy in continuous data. Quantitative data were expressed as a mean or median. For normally distributed quantitative variables, the two groups were compared using a student t-test. However, the Mann-Whitney test was employed to compare the two groups for quantitative data that were not normally distributed. At the 5% level, the results’ significance was assessed.

RESULTS

There was no statistically significant difference between both groups regarding hemoglobin levels, white blood cell counts, platelet counts, liver enzymes (ALT and AST), AFP, INR, albumin, and total bilirubin levels. Also, there was no statistical difference between both groups regarding FIB-4 levels. (Table 1) MDSC levels in HCV-treated individuals were found to be considerably higher. In the HCV-treated group, the median number of MDSCs was 5, with an interquartile range (IQR) of 3.79-7.69. In contrast, the median for the control group was 3.1, with an IQR of 1.4-3.2 (P˂0.001), as shown in Table 2 and Figure 4.

TABLE 1
Comparison between the two studied groups according to demographic data and laboratory investigations.

Parameter	Treated HCV (n=55)	Control group (n=55)	Test of significance	P
Age (years)	48.7±9.5	48.4±8.5	t=0.211	0.833
Mean ± SD
Sex
Males	32 (58.2%)	30 (54.5%)	χ2=0.147	0.700
Females	23(41.8%)	25 (45.5%)
FIB-4	0.62 (0.52-0.87)	0.69 (0.54-0.89)	U=1439.5	0.667
Median (IQR)
Leucocytic count (x103 cell/mm3	6.2±1.8	5.7 ± 1.5	t=1.546	0.125
Mean ± SD
Lymphocytic count (%)	38.5 ± 6.6	36.9 ± 6.5	t=1.244	0.216
Mean ± SD
Platelet count (/mm3)	281 (191-356)	249 (222-345)	U=1480	0.849
Median (IQR)
ALT (U/L)	22 (18-26)	21 (18-24)	U=1285	0.174
Median (IQR)
AST (U/L)	18 (15-21)	19 (13-21)	U=1502	0.95
Median (IQR)
Creatinine (mg/dL)	0.8 (0.71-0.89)	0.86 (0.72-0.93)	U=1389.50	0.465
Median (IQR)
AFP (ng/mL)	3.11 (1-5.1)	3 (2.1-4.0)	U=1429.5	0.624
Median (IQR)
INR	1.01 ± 0	1 ± 0	t=1.37	0.86
Mean ± SD
Total bilirubin (mg/dL)	0.8 (0.7-0.9)	0.9 (0.72-0.97)	U=1192.5	0.056
Median (IQR)
Albumin (g/dL)	4.2 (3.9-4.4)	4.2 (4-4.5)	U=1275.5	0.158
Median (IQR)

• SD: standard deviation; t: Student t-test; U: Mann-Whitney test; χ2: chi-square test; P: P value for comparing the two studied groups; *statistically significant at P≤0.05.

TABLE 2
Comparison between the two studied groups according to MDSC levels.

MDSC	Treated HCV (n=55)	Healthy control (n=55)	Test of Sig	P
Mean ± SD.	6±3.4	2.5±1	U=366.50*	<0.001*
Median (IQR)	5 (3.79-7.69)	3.1 (1.4-3.2)

• 0SD: standard deviation; U: Mann-Whitney test. P value for comparing the two studied groups. *Statistically significant at P≤0.05.

FIGURE 4
Comparison between the two studied groups according to myeloid-derived suppressor cell (MDSC) levels. MDSC: myeloid derived suppressor cells; HCV: hepatitis C virus.

DISCUSSION

As it is well known, Egypt formerly had the greatest prevalence of HCV infection, possibly as a result of the widespread use of unsafe intravenous injections to treat schistosomiasis throughout the 1950s and 1980s¹⁷. The Egyptian government launched a nationwide HCV treatment program in 2018 with a massive effort to identify and treat all HCV-infected people and is currently approaching HCV elimination¹⁷. This has led to an improvement in the patients’ quality of life, cutting down mortality as well as saving future hospitalization burdens that result from long-term sequelae of HCV.

A less fortunate proportion of the patients who received HCV treatment after liver cirrhosis has already developed will still suffer from the long-term sequelae of liver decompensation as well as HCC, despite viral eradication^18,19. Whether patients who received HCV eradication therapy before developing liver cirrhosis may still suffer from HCV sequelae, including HCC is still debatable.

To stumble on this area of debate, numerable research aimed to explore genetic as well as immunological mechanisms to which post-HCV cure carcinogenesis could be attributed. Immune-surveillance malfunction secondary to continuous viral replication with immune system escape unleashes a crucial cause for HCC development post-HCV cure²⁰. MDSCs are a diverse population of myeloid progenitors produced from bone marrow that do not develop into mature myeloid cells¹. Under normal conditions, MDSC expression is low; however, it increases in pathological conditions such as chronic infection, cancer, and autoimmune diseases and is closely related to disease progression and the clinical stage of the disease⁹.

Recent research has reported that the percentage of MDSCs increases in chronic HCV-infected patients and might be related to persistent viral replication^21-23. Furthermore, among individuals with HCV infection, the frequency of M-MDSCs was higher than that of G-MDSCs. These findings imply that HCV infection could cause the proliferation of M-MDSCs¹¹. Activated MDSCs utilize a variety of ways to generate an immunosuppressive microenvironment, producing anergy in NK cells as well as CD4+ and CD8+ T-cells and thereby generating an immune tolerance effect²⁴.

MDSCs have a twofold function: early during infection, they benefit and protect the host by lowering immune-mediated pathology caused by collateral damage in conjunction with robust anti-pathogen immunological responses. Later, they suppress or limit the generation of effective immune responses to pathogens, allowing pathogens to survive and cause long-term infections²⁵.

But, to date, little is known about the time required for these cells to normalize after viral eradication in non-cirrhotic individuals, driven stimuli other than viral replication, and possible implication in progression to HCC in such patients.

In this study, we aimed to investigate the frequency of MDSCs (CD33+, CD11b+, and HLA-DR-) in patients with a previous history of HCV without liver cirrhosis 2 years after viral eradication using DAAs. The study was done on 55 patients and 55 healthy controls. The MDSC population was found to be significantly higher in patients two years after HCV cure than in healthy controls.

With reference to previous work by Abdul Samad B et al., although DAA’s treatment led to a significant reduction in the MDSC population compared to untreated HCV patients, the reduction after confirming SVR was only partial as the population was still significantly higher than in the control group²⁶. This was attributed to the incomplete normalization of IFN-gamma levels post-treatment. In the current study, MDSCs’ mean, although lower than the mean observed by AbdulSamad et al., has not yet fully returned to normal, as demonstrated by the significant increase compared to the control group, although we measured cells after 2-3 years from viral eradication. The time post-SVR in the fore-mentioned study was not mentioned; however, the duration of conduction postulates an earlier timing post-SVR comparable to our study.

It has been observed that DAA treatment significantly lowers inflammatory indicators in the liver and plasma. The fact that this claimed reduction would not reach normal levels, however, could be due to a number of virus-related factors, including the host’s immune system and age, as well as the virus’s genotype, viral load, and chronicity of infection²⁷.

In a small cohort study involving 18 patients co-infected with HIV and HCV, Tumino et al. examined the impact of DAAs on MDSCs and T regulatory (T-reg) cells. Their findings were intriguing, showing that while DAAs improved sustained virologic response rates in patients with chronic HCV infection, they were unable to return the frequency of MDSC and T-reg cells to normal²⁸.

Also, Langhan’s et al. reported the persistence of high levels of T-reg cells in chronic HCV patients who received a full DAA treatment protocol and achieved a sustained virologic response even after 51±14 weeks from the end of therapy²⁹. Telatin and his collaborators, who included 40 subjects who achieved SVR, of which 10 achieved SVR for 48 weeks or more, noticed a partial and late decrease in the percentages of M-MDSCs after viral eradication using DAAs³⁰.

The strength of this study lies in that it detects failure of immune restoration 2-3 years after successful HCV eradication, which, to our knowledge, is a longer duration than previously stated by other studies. However, longer periods of follow-up are still needed to elucidate if MDSCs return to normal following DAA treatment. Limitations of this study include that we did not include patients with advanced fibrosis and cirrhosis. Our aim was to avoid the effect of cirrhosis itself on the MDSC levels. We recommend similar studies to be performed on patients with advanced fibrosis and cirrhosis. Furthermore, studying the effects of our findings, including their postulated contribution to later HCC occurrences, is crucial.

CONCLUSION

Successful DAA therapy leads to slow and partial immunological reconstitution, as demonstrated by the failure to attain normal levels of MDSCs two years after successful HCV eradication despite the normalization of laboratory parameters as well as the absence of liver fibrosis. The clinical implications of these findings should be thoroughly studied. Studying this issue among patients with advanced fibrosis and cirrhosis is recommended. Whether MDSCs would return to normal levels after a longer period of time or not should be explored.

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• Disclosure of funding: self-funded.
• Declaration of use of artificial intelligence: none

Publication Dates

• Publication in this collection
  19 July 2024
• Date of issue
  2024

History

• Received
  09 Jan 2024
• Accepted
  06 May 2024