Antigen peptide transporters are upregulated in squamous cell carcinoma of the oral tongue and show sex‑specific associations with survival
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- Published online on: September 21, 2022 https://doi.org/10.3892/ol.2022.13510
- Article Number: 390
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Copyright: © Attaran et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Squamous cell carcinoma of the head and neck (SCCHN) arises from the mucosal epithelium of the oral cavity, pharynx and larynx and is the most prevalent malignancy involving the head and neck region (1,2). The incidence of this cancer type is increasing globally and is expected to rise by 30% by 2030, corresponding to 1 million new cases annually (1). Despite improvements in treatment modalities resulting in improved local control, the long-term overall survival rates have only improved modestly over the last three decades (1,2).
Cancer is driven by the accumulation of mutations and subsequent clonal selection (3). Peptides derived from cancer-specific mutations can be loaded onto human leukocyte antigen class I molecules (HLA-I) and displayed on the cell surface as cancer antigens, or neoantigens. The recognition of neoantigens by CD8+ T-cells elicits an anticancer immune response. To evade immune recognition and destruction, tumor cells develop escape mechanisms that inhibit anti-tumor cell immunity, such as activating the PD-1/PDL-1 immunosuppressive system, altering the functions of T-cell-priming dendritic cells, depleting antigens, or downregulating the class I antigen presentation machinery (APM) (4). The APM consists of molecules involved in the multistep peptide-presentation process (5) and deficiency in APM components has been reported in many cancer types, including SCCHN. However, the frequency of APM component reduction varies with cancer type and between studies, ranging from 0 to 93% (6).
One of the most extensively studied APM components is the transporter associated with antigen processing (TAP) (7). TAP is a heterodimer comprised of TAP1 and TAP2, and is responsible for transporting short peptides from the cytosol into the endoplasmic reticulum, where together with other chaperones it forms the peptide loading complex. TAP is also involved in transporting peptides into phagosomes and endosomes during cross-presentation in dendritic cells (8). There is evidence that deficiency of TAP in tumor cells allows evasion of immune surveillance and increases tumorigenesis (9). In patients with SCCHN, loss or downregulation of TAP in tumor cells occurs with a frequency ranging from 28 to 71% for TAP1 and 9 to 88% for TAP2 (10–13). Limited and conflicting results have also been reported for TAP levels and clinicopathological factors or survival outcome. Ferris et al (14) showed that the frequency of APM defects in maxillary carcinoma is higher than that in laryngeal and tonsillar carcinoma. Therefore, it is likely that in addition to the differences in staining/scoring methods and/or the investigated patient cohort, the anatomic subsite of tumors also accounts for the varying frequencies of TAP defects reported.
SCC of the oral tongue (SCCOT) is the most common intraoral subsite for SCCHN. Previously, we showed that TAP1 mRNA is progressively upregulated from control tissue to tumor-free tissue in SCCOT patients to SCCOT tumor samples (15). Notably, low levels of TAP1 mRNA in tumor-free samples taken contralateral from the SCCOT associated with better patient survival, whereas no correlation to survival was seen for TAP1 levels in tumors (15). Given that TAP is constitutively expressed and that levels are relatively high in many hematopoietic cells (6), our whole tissue-based findings are insufficient for evaluating the role of TAP in SCCOT cells for shaping immune evasion. As immunotherapy has emerged as a prominent treatment option (16,17), understanding immune evasion mechanisms is important for the design and selection of appropriate immune-restoring strategies. Therefore, we set out to measure protein levels of TAP1 and TAP2 in patients with SCCOT and benign tongue lesions to gain further insight into TAP expression in tumor cells to clarify whether downregulation of TAP is a frequently adopted strategy of tumor cells to reduce their neoantigen presentation.
Materials and methods
Patient material and ethical approval
The current study comprised tongue tissue samples from 95 patients, of whom 17 had benign hyperplastic lesions and 78 had SCCOT. Of the SCCOT patients, 37 were men and 41 women with a median age of 64 years at diagnosis (range 19–89 years). All patients were treated at Otorhinolaryngology and Head & Neck Surgery and Oncology at Umeå University Hospital in Umeå, Sweden. The clinicopathological characteristics of SCCOT patients are presented in Table I. The minimum follow-up time was 5 years for SCCOT patients with status ‘alive disease-free’. Archived formalin-fixed, paraffin-embedded (FFPE) tissue from Clinical Pathology, Umeå University Hospital was used. The project was performed according to the principles of the Declaration of Helsinki after approval by the Regional Ethics Review Board, Umeå, Sweden (Dnr 03-201 and Dnr 08-003 M). Patient samples were anonymized and no written consent was required as archived tissue was used in this study.
 | Table I.Clinicopathological features of the patients with squamous cell carcinoma of the oral tongue (n=78). |
Immunohistochemistry and scoring
Tissue sections (4 µm) were stained with a TAP1 polyclonal antibody (1114-1-AP, Proteintech, Chicago, IL, USA) or a TAP2 polyclonal antibody (ASJ-BB69A9; Nordic BioSite, Sweden) at a dilution of 1:100 and 1:50 respectively in an automated Ventana Benchmark Ultra staining machine with the ultra-VIEW DAB Detection Kit for visualization (Ventana Medical Systems, Inc., Tuscon, AZ, USA) according to the supplier's recommendations. Lymphocytes were used as internal positive controls. The stained samples were photodocumented using a Pannoramic 250 Flash III scanner (3DHISTECK Ltd., Hungary).
The proportion of epithelial cells stained with each antibody was categorized into six groups: 1=0-4%, 2=5-19%, 3=20-39%, 4=40-59%, 5=60-79%, and 6=80-100%. Staining intensity was divided into four levels: 0=negative, 1=weak, 2=intermediate, and 3=strong. The QuickScore (18) was calculated by multiplying the proportion and the intensity scores (range 0 to 18). Cells were scored independently by three of the authors (N.A., X.G. and K.N.). Cases with discrepant scoring were discussed to provide a consensus score.
Worst pattern of invasion (WPOI) and lymphocytic response (LR) at the host/tumor interface were evaluated according to Brandwein-Gensler et al (19). WPOI was divided into five grades: 1=Broad pushing invasive front; 2=Broad pushing fingers; separate tumor islands; 3=Invasive islands (>15 cells/island); 4=Invasive islands (<15 cells/island), including single cell invasion; 5=Tumor satellites ≥1 mm distance from tumor. LR was divided into three grades: 1=Continuous dense rim of lymphoid tissue; 2=Patches of discontinuous dense lymphoid infiltrate; 3=Limited or no response.
Statistical analysis
Correlations between categorized clinicopathological variables and categorized TAP levels were determined by Fisher's exact test. For continuous variables, correlations were studied using nonparametric Spearman correlation analysis and the correlation coefficient (rho) was calculated to evaluate correlation strength. Nonparametric Mann-Whitney U test was used to study the difference between two groups of continuous variables. The Kaplan-Meier method with log-rank test was performed to estimate the impact of TAP levels on patient survival. Three survival measures were analyzed: overall survival (time from date of diagnosis to death from any cause), cancer-specific survival (time from diagnosis to death due to SCCOT) and disease-free interval (time from completion of treatment to date of relapse or death). All tests were conducted in IBM SPSS Statistics 26 (IBM Corp., Armonk, NY, USA). A two-sided P-value <0.05 was considered significant.
Results
TAP1 and TAP2 levels in SCCOT and benign lesions
Cytoplasmic TAP1 was detectable in all SCCOT specimens (n=78). The proportion of TAP1 expressing tumor cells was graded 6 (80–100% of the tumor cells expressed TAP1) in 76 cases and 5 (60–79% of the tumor cells expressed TAP1) in 2 cases. Staining intensity of TAP1 was scored as weak, intermediate and strong in 20 (25.6%), 52 (66.7%) and 6 (7.7%) SCCOT, respectively. In benign hyperplastic lesions (n=17), the proportion of TAP1 expressing cells varied from 1 to 4, and intensity was graded as weak in all but one of these benign lesions. The resulting QuickScores for TAP1 were compared between SCCOT and benign lesions. The majority of SCCOT lesions had a QuickScore of 12 (51 samples, 65.4%), whereas most benign lesions had a QuickScore of 3 (9 samples, 52.9%), showing a significant increase in TAP1 levels in SCCOT compared to benign lesions (P<0.001, Mann-Whitney U test, Fig. S1A).
Due to the limited volume of some samples, TAP2 staining could not be performed on four cases of SCCOT and three benign lesions. Similar to TAP1, cytoplasmic TAP2 was detected in all SCCOT specimens, and the proportion of TAP2-positive tumor cells was graded as 6 in 72 lesions and 5 in 2 lesions. Weak, intermediate and strong TAP2 expression was seen in 17 (23.0%), 51 (68.9%) and 6 (8.1%) SCCOT lesions, respectively. In the 14 benign lesions analyzed, the proportion of TAP2-expressing cells varied from 2 to 6 and the intensity was weak in all but one of the lesions. Histograms of TAP2 QuickScore (Fig. S1B) showed that the majority of SCCOT lesions had a QuickScore of 12 (50 samples, 67.6%) and the majority of benign lesions a QuickScore of 3 (6 samples, 42.9%). Mann-Whitney U test showed that TAP2 was significantly upregulated in SCCOT compared to benign lesions (P<0.001). A close correlation between TAP1 and TAP2 QuickScores was identified (rho=0.640, P<0.001). Representative staining results for TAP1 and TAP2 are shown in Fig. 1.
Correlations between clinicopathological factors and TAP intensity
Due to the variance in TAP1 intensity between SCCOT lesions we continued to investigate whether there were associations between clinicopathological factors and staining intensities. Patients were divided into two groups: TAP1-intermediate/strong and TAP1-weak. TAP1 intensity did not associate with clinicopathological factors such as age, sex, T stage, nodal status, TNM stage, WPOI, LR or degree of differentiation. Similarly, no correlations between clinicopathological factors and TAP2 intensity were found (Table II, P>0.05 for all comparisons).
Impact of TAP intensity on patient survival
Kaplan-Meier curves with log-rank test was performed to compare survival between patients with intermediate/strong and weak TAP1 expression. No significant differences were observed for overall survival (P=0.530), cancer-specific survival (P=0.888) or disease-free interval (P=0.657) (Fig. 2). Similar results were observed for TAP2 on overall survival (P=0.084), cancer-specific survival (P=0.278) and disease-free interval (P=0.428).
Next, we investigated whether there was a TNM stage- or sex-specific impact of TAP. In our cohort, there was a significant difference in age between male and female patients with early-stage tumors (stage I and II) (Table SI, P=0.001). To have age-wise comparable groups of females and males, only patients under 70 years were analyzed, showing significant differences in overall survival (P=0.002), cancer-specific survival (P=0.005) and disease-free interval (P=0.011) between males (n=19) and females (n=11) (Fig. 3).
Further division of patients into four groups according to sex and TAP1 intensity, varying degrees of differences in overall survival (P=0.009), cancer-specific survival (P=0.046) and disease-free interval (P=0.066) were identified (Fig. 4A, C and D). The best overall survival was seen in males with intermediate/strong TAP1 (n=17) which is distinct to TAP1-weak males (n=2), TAP1-intermediate/strong females (n=7) and TAP1-weak females (n=4). Similarly, the best overall survival was seen in males with intermediate/strong TAP2 (n=13) compared to TAP2-weak males (n=4), TAP2-intermediate/strong females (n=9) and TAP2-weak females (n=1) (Fig. 4B and F). No correlations between sex and other clinicopathological factors were found (data not shown).
Discussion
The immune system has the capacity to fight cancer, however, cancer cells can evade immune elimination through a wide range of mechanisms. Loss of antigen presentation due to mutations, transcriptional downregulation, hypermethylation and/or loss of heterozygosity (LOH) in APM components have been reported as immune escape mechanisms in cancers (4). In the current study, we showed that TAP1 and TAP2 levels are closely correlated and that SCCOT contained higher levels of TAP than hyperplastic tongue lesions. Criteria established by the HLA and cancer component of the 12th International Histocompatibility Workshop suggest that proteins with a percentage of stained tumor cells <25%, 25–75% and >75% are scored as negative, heterogeneous or positive, respectively (20). According to this criterion, we conclude that TAP in all but two of our investigated SCCOT samples are ‘positive’. Considering staining intensity, no distinct clinicopathological characteristics or survival outcome were found between TAP-intermediate/strong and TAP-weak patients. Taken together, it seems that loss of TAP expression is not an underlying mechanism of tumor immune evasion in SCCOT.
In their analysis of 89 patients with SCCHN, Feenstra et al (10) reported that decreased TAP1 and TAP2 staining intensity in tumor cells compared to the surrounding stromal cells was seen in 28 and 9% of patients, respectively. In another 25 patients with SCCHN, loss or downregulation of TAP1 and TAP2 (<75% tumor cells) was found in 52 and 88% of the lesions, respectively (11). In a study of 25 patients with SCCHN, loss or downregulation of TAP1 and TAP2 was found in 68 and 64% of the lesions, respectively (12). In 51 patients with laryngeal SCC, decreased expression of TAP1 was found in 71% of patients (13). Obviously, our results from 78 patients with SCCOT are inconsistent with most previous SCCHN studies. Even if differences in staining methods and evaluation could lead to variations between different studies, the most likely explanation is that we studied tumors and benign tissues located in the oral tongue only, based on previous findings of subsite-based differences in protein and RNA expression clearly indicating wide differences in tumor phenotypes at different subsites in the head and neck and even within the oral cavity (14,21,22).
Earlier small-cohort studies have shown that LOH at the HLA-I loci on chromosome 6 is a frequent event in cancers (4). Recently, investigation of 83,644 cancer samples revealed that HLA-I LOH was present in 17% of patients, with a range of 2–42% across different tumor types (23). Within the 1,134 patients with SCCHN included in that study, the prevalence of HLA-I LOH was 27.2% (23). More recently, Garrido et al (24) reported that copy-neutral LOH affecting the entire chromosome 6 is a frequent mechanism of HLA-I alterations in cancer. On the other hand, analysis of The Cancer Genome Atlas (TCGA) database for 10,967 patients with different types of cancer revealed that approximately 5% harbor homozygous deletions or truncating mutations in APM components (4). Therefore, LOH at HLA-I, which could reduce the diversity of the presented peptide repertoire, seems to be a more common mechanism for cancer immune escape (4). Importantly, in addition to HLA-I, genes encoding class II and class III HLA, and several components of APM are also located on the short arm of chromosome 6, including TAP1 and TAP2. Ciani et al (25) analyzed allele-specific genomic data derived from TCGA, including 334 patients with SCCHN, to elucidate the role of copy-neutral LOH and somatic gain in cancer. From their results of HLA-I and TAP, concordant copy-neutral LOH occurs in 14% and concordant gain of copy number in 29% of tumors without sex difference. Therefore, during the evolutionary process of cancer development, alterations in haplotype and copy numbers in chromosome 6 might provide selective advantage to the tumor cells to escape immune recognition. Even though the levels of TAP proteins remain ‘positive’ in our cohort of patients with SCCOT, their ability to present cancer antigens on the cell surface might be compromised due to chromosome 6 LOH or copy number alterations.
Overall, no significant correlations between TAP levels and clinicopathological features were found in this study. Comparing TAP-weak to TAP-intermediate/high patients in survival outcome in general, we failed to identify any differences. This result is consistent with our previous findings that TAP1 mRNA levels in tumor samples are not associated with patient survival. However, focusing on patients under 70 years with early stage SCCOT, we found that males had better survival than females. Garavello et al (26) reported that sex does not influence prognosis in patients with oral tongue cancer and Roberts et al (27) found no evidence of sex-related survival disparities among SCCHN patients, even when the analysis was restricted to individual anatomic sites. In a recent large cohort study, Mazul et al (28) showed that females with non-oropharyngeal HNSCC had better five-year overall survival than males. Therefore, our finding that males had better survival than females is surprising. As male patients with intermediate/strong TAP intensity displayed distinct survival outcome compared to female patients, we suggest a sex-specific impact of TAP on survival. It seems that males could gain from higher expression of the TAP proteins. Sex differences in immune response have long been recognized (29). Recently, Castro et al (30) found that younger and female patients accumulate driver mutations in their tumors that are less readily presented compared to males and older patients, suggesting that the strength of immune selection during tumor development varies with sex and age. Considering TAP, more patients should be studied to elucidate its sex-specific impact on patient survival.
In summary, this is the first study of TAP proteins in a cohort of patients with SCCOT. Results showed an increase of TAP in tumor cells and provide further evidence for sex-specific immune modulation in cancer. With immunotherapy being more and more used in cancer treatment one could thus speculate whether increasing TAP expression could be a useful immune-restoring strategy at least in male patients.
Supplementary Material
Supporting Data
Supporting Data
Acknowledgements
Not applicable.
Funding
The present study was supported by Lion's Cancer Research Foundation, Umeå University; The Swedish Cancer Society (contract number 20 0754 PjF 01H); Umeå University; Region Västerbotten; Ministry of Health Czech Republic, conceptual development of research organization (MMCI, 00209805).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
NA performed experiments, analyzed data and wrote the manuscript. PJC interpreted data, wrote and edited the manuscript. KZ, BE and MM provided medical materials, interpreted data and reviewed the manuscript. NS interpreted data and reviewed the manuscript. KN supervised the project, performed experiments, and wrote and edited the manuscript. XG supervised the project, performed experiments, analyzed data, and wrote and edited the manuscript. All authors read and approved the final manuscript. NA, KN and XG confirm the authenticity of all the raw data.
Ethics approval and consent to participate
Ethical permission for the study has been granted by the Regional Ethics Review Board, Umeå, Sweden (DNR 03-201, 08-003M) and the project was performed according to the principles of the Declaration of Helsinki. Written consent is not required for the use of surplus archived tissue samples.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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