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ORIGINAL ARTICLE
Ahead of print publication  

Downregulation of human leukocyte antigen Class I expression: An independent prognostic factor in colorectal cancer


1 Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
3 Department of Immunology, Medical School, Shahid Beheshti University of Medical Sciences, Research Institute for Gastroenterology and Liver Disease, Shahid Beheshti University of Medical Sciences, Tehran, Iran
4 Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
5 Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Tehran, Iran

Date of Submission01-Jul-2018
Date of Acceptance11-May-2019
Date of Web Publication09-May-2020

Correspondence Address:
Mohammad Reza Zali,
Research Institute for Gastroenterology and Liver Disease, Shahid Beheshti University of Medical Sciences, P.O. Box: 19857-17411, Yeman Street, Chamran Expressway, Tehran
Iran
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_429_18

 > Abstract 


Aim: In the present study, we evaluated the clinical prognostic value of human leukocyte antigen (HLA (Class I tumor cell expression in a series of colorectal cancer (CRC) patients and also explored the association of this expression profile with molecular features such as mutation status of KRAS and BRAF, microsatellite stability status, and clinicopathological characteristics of the patients.
Patients and Methods: Formalin-fixed paraffin-embedded tumor tissue of 258 CRC patient's sections were immunohistochemically stained and subsequently quantified for HLA Class I expression by the tumor cells. Determination of microsatellite instability (MSI) tumor status was ascertained using mononucleotide repeat microsatellite targets. KRAS and BRAF mutations were screened by polymerase chain reaction (PCR)-sequencing and cast-PCR, respectively.
Results: HLA Class I expression was normal in 91 cases (35.3%), downregulated in 119 (46.1%), and loss of expression in 48 (18.6%) cases. Forty (15.5%) tumors were MSI-H (MSH), 49 were MSI-L (19%), and 169 were microsatellite stable (MSS) (65.5%). Thirty-six (14%) and 15 (5.8%) of the patients exhibited mutation in the KRAS and BRAF, respectively. It was found that patients with downregulated expression of HLA Class I were associated with Stage II tumors (P < 0.001) and a MSS tumor status (P < 0.001), while patients with loss of expression were associated with MSH status (P < 0.001). Univariate and multivariate analyses revealed that HLA Class I downregulated expression was an independent prognostic parameter for shorter overall patient survival time (hazard ratio: 1.8, P = 0.003).
Conclusions:HLA Class I expression is an independent and sensitive clinical prognostic marker that might be used in CRC patients.

Keywords: Clinicopathological characteristics, colorectal neoplasms, human leukocyte antigen, microsatellite instability, survival analysis



How to cite this URL:
Nazemalhosseini-Mojarad E, Asadzadeh-Aghdaei H, Mohammadpour S, Esfahani AT, Porhoseingholi MA, Molaei M, Jalali A, K. Kuppen PJ, Zali MR. Downregulation of human leukocyte antigen Class I expression: An independent prognostic factor in colorectal cancer. J Can Res Ther [Epub ahead of print] [cited 2020 Aug 10]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=284078




 > Introduction Top


Recent advances in knowledge on the biology of cancer cells have demonstrated that the adaptive immune system might play a critical role in controlling tumor progress and eliminating metastasis cells, especially in solid tumors.[1],[2] Antitumor immune responses are mediated mostly by cytotoxic T-lymphocytes (CTL),[1] which require the expression of human leukocyte antigen (HLA) Class I in the (pre)-neoplastic target cells.[2] Tumors with downregulated HLA Class I expression might escape from CTL-mediated elimination.[1],[3],[4] This event has been reported in a variety of malignancies and is commonly related to the histopathological characteristics and clinical courses of the disease.[5],[6],[7],[8],[9] In addition, a variety of HLA expression status has been defined in human tumors, such as HLA total loss, HLA haplotype loss, HLA-specific locus downregulation, HLA allelic losses, and a combination of these phenotypes. Genetic instability is a feature of tumor cells, resulting in genetic heterogeneity of tumors, which is considered as the driving force in selection and outgrowth of immune escape variants in tumors.[10],[11],[12] Several studies described HLA Class I expression levels in cancer, mostly determined by immunohistochemistry, and its correlation with patient's survival and clinical impact, with rather controversial outcomes.[13],[14],[15],[16],[17],[18],[19],[20] Recent studies have suggested that molecular subtypes of colorectal cancer (CRC) may show differences in clinical outcomes and overall survival.[21],[22],[23] Therefore, results of HLA Class I tumor expression obtained from a CRC population without considering molecular subtypes might not provide precise insight into patients' survival. This study evaluated the prognostic value of HLA Class I expression in a series of CRC tumors, in association with mutation status of KRAS and BRAF, and microsatellite stability status.


 > Patients and Methods Top


Study population

A randomly-selected group of 258 curatively-operated CRC patients were enrolled in this study from February 2004 to October 2014. The median age of the patients was 56 years (range: 28–88 years; standard deviation [SD]: 11 years). [Table 1] represents clinical and histopathological information. This historical cohort was collected from the CRC Unit Database, Department of Cancer Prevention, Gastroenterology and Liver Disease Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Tumors were evaluated for location, stage, differentiation grade, and mucinous characteristics as described in the hospital records of the patients. Tumor staging was determined using the tumor-node-metastasis (TNM) classification and categorized according to the WHO classification, as well-differentiated (G1), moderately-differentiated (G2) or poorly-differentiated (G3). Mucinous differentiation was defined as fully/partly or no mucinous differentiation. Written informed consent was obtained from the patients and the Medical Ethical Committee of Research Center for Gastroenterology and Liver Disease approved the study protocol in accordance with the principles of the Helsinki Declaration (Ethic NO: IR.SBMU.RIGLD.REG.1391.681). The patient follow-up procedure was completed until March 2015. The mean follow-up time was 8 years (median: 5.4 years; range: 0.1–18.6 years, SD: 5.2 years).
Table 1: Clinicopathological and demographic features of 258 colorectal cancer patients according to the human leukocyte antigen Class I expression profile

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Genetic marker analyses

DNA isolation

Serial sections (5 μm) from formalin-fixed paraffin-embedded matched (FFPE) normal and tumor tissues were routinely stained (hematoxylin/eosin staining), and representative normal and tumor regions were identified by microscopic examination by an expert pathologist. Genomic DNA from each tumor and corresponding normal tissue were purified using the QIAamp DNA FFPE Tissue Kit (QIAGEN GmbH, Germany). Yield and purity of the products were determined by electrophoresis on 0.8% agarose gel and spectrophotometry absorbance at 260 nm, respectively.

Microsatellite instability analysis

The microsatellite instability (MSI) status was determined using five mononucleotides repeat microsatellite targets (BAT25, BAT26, NR21, NR24, and NR27) using standard polymerase chain reaction (PCR) techniques.[8] PCR products were denatured by electrophoresis on 5% denaturing polyacrylamide gels and analyzed by an ABI 3130xl automated sequencer (Applied Biosystems, USA). Tumor samples exhibiting different allele peaks than the corresponding normal samples were classified as MSI for that particular marker. MSI-H was defined when at least two of the five standard markers showed instability in tumor DNA. MSI-L was defined when one MSI marker show instabilit and others were microsatellite stable (MSS). Analysis was performed twice if the results were ambiguous.

KRAS and BRAF mutations

For each sample, codons 12, 13, and 61 of the KRAS Gene, and codon V600E of the BRAF Gene were screened by Pyrosequencing and Competitive Allele-Specific TaqMan PCR (Cast-PCR), respectively. Pyrosequencing of KRAS codons 12, 13, and 61 was performed using the Therascreen KRAS Pyro Kit (QIAGEN) by manufacture's protocols. For pyrosequencing preparation, KRAS was first amplified by primers, one of which was biotinylated to immobilize with streptavidin beads (GE healthcare). PCR-pyrosequencing reaction was carried out on thermocycler (Eppendorf), containing 10 ng of genomic DNA. Two sets of the seq primer (Therascreen KRAS Pyro Kit QIAGEN) were used to analyze mutations in codons 12, 13, and 61. Pyromark Q24 version 2 software (QIAGEN, Hilden, Germany) was applied to analyze pyrosequencing results. Detection limit for KRAS mutations was obtained as 3% according to the Therascreen KRAS Pyro Kit (QIAGEN) kit. Cast-PCR™ was performed in 20-μl reactions comprising 50 ng DNA template, 1X Genotyping Master Mix (Applied Biosystems), and 1X of TaqMan Mutation detection assays. PCR was run on a real-time PCR (7500 ABI). Cycling conditions were as follows: one cycle consisting 95°C for 10 min, followed by 5 cycles of 92°C for 15 s, 58°C for 1 min, 45 cycles, 92°C for 15 s, and 60°C for 1 min.

Immunohistochemistry and evaluation of staining

Tissue sections were immunohistochemically stained for HLA Class I using the monoclonal antibodies (mAbs) against HCA2 and HC10. The HCA2 and HC10 mAbs were applied in immunohistochemistry as hybridoma culture supernatant, kindly provided by Prof. J. J. Neefjes from the Netherlands Cancer Institute (Amsterdam, The Netherlands). The reactivity spectrum of HCA2 mAb includes HLA-A (except HLA-A24), HLA-B73, and HLA-C molecules as well as HLA-E, HLA-F, and HLA-G antigens.[20] HC10 reacts with HLA-B and HLA-C molecules and HLA-A10, -A28, -A29, -A30, -A31, -A32, and -A33 heavy chains.[8] FFPE tumor tissue was sectioned (5 μm) and prepared on poly-L-lysine (Sigma-Aldrich P8920)-coated slides and dried overnight at 37°C for 24 h. The blocks were deparaffinized in xylol for 15 min and subsequently rinsed in ethanol. Endogenous peroxidase was blocked for 15 min in 10% hydrogen-peroxide methanol, and subsequently, the sections were rinsed in deionized water. Antigen retrieval for the markers consisted of boiling the tissue sections in sodium citrate buffer (10 mM sodium citrate, 0.05% Tween 20, pH 6.0) for 24 min at a microwave with power 800 Watts and then rinsed in Tris-buffered saline (TBS). Blocking serum (5% horse serum in phosphate-buffered saline [PBS]) was added to slides for 15 min. Subsequently, the sections were washed in PBS for 10 min and incubated overnight at room temperature with one of the mAbs against HCA2 or HC10. After overnight incubation with the markers, the sections were washed in TBS for 15 min and incubated with mouse Envision + visualization system (Dako) for 30 min. Then, sections were washed in PBS for 15 min and developed in 3,3-di-aminobenzidine tetrahydrochloride with 0.002% hydrogen peroxide for 10 min, resulting in a brown signal. Finally, the slides were rinsed in water, dehydrated in alcohol, and counterstained with hematoxylin. The percentage of the tumor cells showing brown staining in each tumor section was enumerated independently by two blinded investigators. HCA2 and HC10 staining was scored in six categories. Essentially, the scoring was divided into quartiles, but for tumors with <25% stained cells, there was a distinction made between those with 6%–25% positively-stained tumor cells, those with approximately 1%–5% positively stained cells, and those with absolute no positively-stained tumor cells.[8] Tissue stromal cells, normal epithelium, or lymph follicles served as positive internal controls to ascertain the quality of the staining. Patients were excluded if positive internal controls of tumors were not stained for HCA2 or HC10. Variations in the percentage of stained cells enumerated by two investigators were within a 10% range. In consideration of the error, we evaluated the percentage of stained tumor cells at 10% levels.

Statistical analysis

The data were analyzed using the SPSS software program for Windows, Release 13.0.0 (SPSS Inc., Chicago, IL, USA). Comparison of variables was performed using Pearson's Chi-square test, Fisher's exact test, or the Mann–Whitney U test, depending on the nature of the data. Two-tailed P < 0.05 was considered statistically significant. CRC overall survival time was computed since the date of cancer diagnosis up to the date of death or end of follow-up (March 31, 2015). Patients who died due to unrelated causes to CRC were censored at the time of death and excluded from further analyses. For survival analyses, the following variables were assessed: age, sex, location of the tumor (colon vs. rectum), TNM stage, and grade of differentiation (well/moderate vs. poor), use of adjuvant therapy, age of diagnosis, family history, and MSI. Overall survival analyses were done through a Cox proportional hazard function for both univariate and multivariate analyses and Kaplan–Meier (log-rank test) curves were plotted. Significance for all statistics was recorded as P < 0.05.


 > Results Top


Patients and tumors

A total of 134 men (51.9%) and 124 women (48.1%) diagnosed with CRC were included in this retrospective study. Characteristics of the patients are shown in [Table 1]. Thirty-six patients (14%), 117 patients (45.3%), 85 patients (32.9%), and 20 patients (7.8%) were in Stages I, II, III, and IV, respectively. Tumor differentiation status could not be assessed in 17 cases (6.6%). Out of the 258 patients, 73 (28.3%) had family history of CRC or other gastrointestinal cancers. According to our findings, 50 patients (19.4%) had metastasis at the time of diagnosis, while 208 were negative for metastatic status. In addition, 28 (10.8%) patients developed metastases during clinical follow-up.

Microsatellite instability and KRAS/BRAF mutations

According to the method used as described in the “Materials and Methods,” 40 (15.5%), 49 (19%), and 169 (65.5%) tumors were found to be MSI-H, MSI-L, and MSS, respectively. Mutation in the KRAS, exon 2 (codons 12 or 13), or exon 3 (codon 61) was found in 36 patients, representing an overall mutation frequency of 14% for KRAS in our study population. In addition, mutation of the BRAF at exon 15 (V600) was found in 15 patients, representing an overall mutation frequency of 5.8% [Table 1].

Human leukocyte antigen Class I expression and clinicopathological parameters

A total of 258 tumors were quantified for HLA Class I expression for both mAbs (HC10 and HCA2) by microscopic evaluation. HLA-Class I expression was normal in 91 cases (35.3%), downregulated in 119 cases (46.1%) and loss of expression in 48 cases (18.6%) [Figure 1] and [Table 1]. The relationship between HLA Class I expression and patient/tumor characteristics was assessed and five significant differences were observed [Table 1]. Downregulated expression of HLA Class I, was present in both left-sided and right-sided tumors (P = 0.003) and the patients were older (P ≤ 0.001). In addition, distribution of tumor stages differed among patients with down, loss, and normal expression tumors (P ≤ 0.001) and HLA Class I loss of expression was correlated significantly with MSI-H (P ≤ 0.001) [Table 1]. No significant association was found among patients with various HLA expression status and tumor differentiation mucinous characteristics, adjuvant therapy, or molecular markers including KRAS and BRAF.
Figure 1: Representative immunohistochemical staining patterns of formalin-fixed paraffin-embedded primary colorectal cancer with human leukocyte antigen Class I antigen. (a) Tumor epithelial cells showing total absence for human leukocyte antigen Class I and only stromal and infiltrative cells show positive staining for human leukocyte antigen Class I. (b) Expression of human leukocyte antigen Class I in <50% tumor cells. (c) Expression of human leukocyte antigen Class I in >50% tumor cells (×20)

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Human leukocyte antigen Class I expression status and clinical outcome

To assess the effect of tumor HLA Class I expression status on survival, we used a Cox regression model for univariate and multivariate analysis. In overall survival, all characteristics that could play a role in prognostic status such as HLA expression status, TNM stage, microsatellite stability status, KRAS and BRAF mutation status, and sex and location of tumor were entered into univariate and multivariate models [Table 2]. Univariate and multivariate analyses revealed that downregulated HLA Class I expression level was an independent predictor for overall survival (hazard ratio: 1.8, P = 0.003). We also obtained Kaplan–Meier curves of overall survival in patients according to HLA Class I expression status. The overall survival time in patients with downregulation of HLA I expression was lower than that of those with HLA loss or normal expression (P = 0.04) [Figure 2].
Table 2: Univariate and multivariable prognostic analysis of overall survival in 258 colorectal cancer patients

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Figure 2: Association of human leukocyte antigen Class I expression into primary tumor lesions with overall survival in patients with colorectal cancer using the KaplanMeier method. Differences in patients survival were analyzed using a log-rank test. The overall survival in patients with human leukocyte antigen downexpression (blue line) was lower than that of those with human leukocyte antigen loss (green line) or normal (yellow line) expression (P = 0.04)

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 > Discussion Top


HLA Class I plays a central role in anticancer immune response, especially as cancer antigen-presenting molecules for CTLs.[2],[4] However, cancer cells might escape from CTLs by downregulation of HLA Class I molecules. Recent evidence have suggested that HLA Class I expression may play a role in the clinical course of the malignancies. In this study, the number of tumors showing loss of HLA Class I expression was similar to some of the previous reports;[2],[16],[24] nevertheless, inconsistent with our findings, there are some studies showing higher expression levels of HLA Class I molecules.[7],[20],[25] Such conflicting data seem to be due to differences in technical approaches, antibodies used, scoring protocols, and diversity in the study populations. The present study demonstrated that CRC patients with downregulated expression of HLA Class I had an independent worse overall survival. Inconsistent with our findings, Speetjens et al. show an independent worse overall survival in rectal cancer patients with high or loss expression.[8] As T-cell-mediated destruction of tumors depends on HLA I expression, downregulation of HLA I molecules leads to defect in immune surveillance and reduced survival.[26] HLA Class I expression was positively associated with depth of tumor invasion in gastric cancer and a combination of HLA Class I expression and Treg cells infiltration may be a prognostic marker and predict response to chemotherapy in gastric cancer,[15] as well as breast tumors.[14] In the case of CRC, a biologically heterogeneous disease, this phenomenon is more complex. CRC is a disease characterized by different types of genetic abnormalities such as mutations, MSI, and aberrant DNA methylation. In our study, we found that tumors with downregulation of HLA Class I were located predominantly in the left colon compared to other sites and were associated with Stage II and MSS status, while tumors with loss of expression were more frequent in patients with MSH and right-sided CRC. Lower mutation rate in KRAS in our study (14%), as compared with other studies,[27],[28],[29] may be attributed to different methodologies and study population. We used pyrosequencing for KRAS mutation detection, which is the most reliable and sensitive technique for mutation detection.[30] Besides, in Iran, the frequency of KRAS mutation has been reported to be between 20% and 60% higher frequency associated with PCR-restriction fragment length polymorphism method (60%) and lower KRAS mutations rate has been detected with sequencing (20%–40%).[27],[28],[29] We found no significant association among patients with various HLA Class I expression and KRAS and BRAF status. In this regard, He et al. evaluated the association of KRAS mutations at codon 12 and levels of human HLA Class I antigen expression in primary lung tumors and metastatic lymph nodes of patients with nonsmall cell lung cancer.[31] They found a negative correlation between KRAS mutations and HLA Class I antigen expression in primary and metastatic tumors. Studies showed that the clinical and molecular characteristics of right and left side colon tumors are different,[32],[33],[34] in addition, right-sided CRCs has better prognosis comparing left sided.[35],[36] Our results suggested that in spite of the cancer heterogenicity and without considering the tumor location, immune feature such as HLA Class I expression level can be an independent predictor for overall survival. In agreement with the correlation with clinical outcome of tumor HLA Class I expression as we found in our study, several studies reported that the tumor HLA Class I expression level might be a clinical prognostic factor for several cancers such as the ovary, breast, endometrial, gastric, and esophageal.[9],[14],[15],[18] Ogino et al. identified HLA Class I downregulation and low CD8+ T-cell infiltration as an independent prognostic marker for unfavorable clinical outcome in multivariate analysis on a series of laryngeal squamous cell carcinoma cases.[17] In concordance with other studies, MSI-H CRC patients had more HLA-I loss frequency. There is growing evidence that the extent of antitumor immune response correlates with the type of genetic instability. Kloor et al. showed that defects of HLA Class I antigen processing and presentation seem to be significantly more frequent in MSIH CRC.[37] de Jong et al. in 2012 documented that endometrial carcinomas (ECs) with loss of mismatch repair protein (MMR) expression had more frequent loss of HLA Class I when compared with ECs with MMR protein normal expression.[5] Thus, loss of HLA Class I expression is a frequent event in MUTYHassociated polyposis carcinomas, syndrome caused by defects in the MUTYH DNA repair enzyme, similarly to MMR deficient colorectal tumors.[38] These results suggest that in MSIH tumors, the immunoselective pressure may lead to the outgrowth of cells with defects of antigen presentation.[37] Today, it is clear that distinct mechanisms are responsible for HLA Class I loss in hereditary nonpolyposis colorectal cancer (HNPCC) and sporadic MSI-H tumors. In HNPCC tumors, loss of HLA Class I is due to mutation or alteration in B2m gene, and in sporadic cases, mutations in antigen processing machinery component lead to loss of HLA Class I expression.[39]

Financial support and sponsorship

The research has been supported by the Research Institute for Gastroenterology and Medical Ethical committee of RCGLD Ethics Committee with the number Ethic NO: IR.SBMU.RIGLD. REG. 1391.681.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

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