PD‑L1 expression in malignant melanomas of the skin and gastrointestinal tract

  • Authors:
    • Michiko Akiyama
    • Yoko Matsuda
    • Tomio Arai
    • Hidehisa Saeki
  • View Affiliations

  • Published online on: January 21, 2020     https://doi.org/10.3892/ol.2020.11325
  • Pages: 2481-2488
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Gastrointestinal melanoma (GM) is a rare but aggressive type of malignant melanoma arising in the gastrointestinal tract. An anti‑programmed cell death protein 1 (PD‑1) antibody markedly improves prognosis in patients with melanoma. However, little is known regarding the expression of immune‑oncology biomarkers in GM compared with skin melanoma (SM), especially in the Asian population. the present study examined clinicopathological characteristics, PD‑L1 and HLA expression, and immune‑oncology marker expression in 10 cases of GM and 31 cases of SM. Patients with GM exhibited significantly higher incidences of lymph node and distant metastases than patients with SM (P=0.0448 and P=0.0247, respectively). The infiltration of CD8+ lymphocytes was significantly higher in GM than in SM (P=0.0231). The infiltration of PD‑1+ lymphocytes was higher in GM than in SM, but the difference was not significant (P=0.0975). PD‑L1‑positive melanoma exhibited a higher proportion of BRAFV600E‑positive melanoma than PD‑L1‑negative melanoma (P=0.0317; 39.4 and 0%, respectively). PD‑L1‑positive melanoma exhibited significantly higher rates of CD8+ and FOXp3+ lymphocyte infiltration than PD‑L1‑negative melanoma (P=0.0221 and P=0.0463, respectively). By contrast, PD‑1+ lymphocytes did not differ between PD‑L1‑positive and ‑negative cases. Furthermore, HLA‑positive melanoma exhibited higher proportions of PD‑1 (P=0.0101; 53.7 and 15.4%) and CD8 than HLA‑negative melanoma (P=0.0818; 66.7 and 38.2%). These results provided useful information regarding tumor immunity in GM and SM and may contribute to the development of treatment strategies for GM.

Introduction

Melanoma is one of the most aggressive tumors (1,2); it is most commonly localized in the skin but can occur at any site where melanocytes exist (3). Gastrointestinal melanoma (GM) is a rare type of malignant melanoma arising in the gastrointestinal tract (46). We have previously reported that GM shows more aggressive features than those of skin melanoma (SM), such as a high mitotic rate and frequent metastases to lymph nodes and distant organs (7). A recently developed immune checkpoint inhibitor (ICI), the anti-programmed death 1 (PD-1) antibody nivolumab, has markedly improved patient prognosis in SM as compared to that observed with the conventional cytotoxic chemotherapeutic agent dacarbazine (8). However, predictive biomarkers for ICIs are needed owing to the potential for resistance and the high cost.

PD-1 is expressed on the surface of cytotoxic T cells, and its ligands programmed death ligand (PD-L) 1 and 2 are expressed on both tumor and immune cells (9). The inhibition of interactions between PD-1 and PD-L1/PD-L2 by an anti-PD-1 antibody causes the reactivation of cytotoxic T cells, leading to the recognition and destruction of melanoma cells (10). Diagnostic immunohistochemical assays of PD-L1 have been approved by the FDA (11), but research is ongoing to better understand the role of PD-L1 as an immune-oncology marker, both alone and in combination with other markers.

Major factors involved in tumor immunity include tumor antigens, inflammation, immune suppression, and host environment. Tumor antigens, which are fragments of DNA, RNA, and protein, are recognized as non-self by the host immune system (12). Inflamed tumors show immune cell activation, especially of CD8+ cytotoxic T cells (13). Immune suppression is mainly regulated by Forkhead box protein 3 (FOXp3)-positive regulatory T cells (14). The host environment, including the microbiome, germline mutations, and human leukocyte antigen (HLA) phenotypes, modulates the immune response (15). Therefore, these factors have been reported as predictive biomarkers for ICI. However, little is known about the expression of immune-oncology biomarkers in GM and SM, especially in the Asian population. In the present study, we investigated the clinicopathological characteristics associated with PD-L1 and HLA expression in tumor cells as well as the degree of tumor-infiltrating lymphocytes in GM and SM.

Materials and methods

Patients and tissues

Tissue samples [GM (n=10) and SM (n=31)] were obtained from patients who underwent surgical treatment at our hospital between 1997 and 2015 (7). This study was conducted in accordance with the principles in the Declaration of Helsinki (2008). Approval for the study was obtained from the human research ethics committees at the Tokyo Metropolitan Geriatric Hospital (No. R17-33) and the Nippon Medical School Hospital (no. 29-07-805).

Tissue processing and histological assessment

Tissues were fixed in formalin and subjected to standard processing and paraffin embedding. They were sliced into 3-µm-thick sections for hematoxylin and eosin (H&E) staining and immunohistochemical analyses. Diagnoses of pathological specimens were made by more than two pathologists based on the American Joint Committee on Cancer (AJCC, 2009) guidelines for SMs and the Union for International Cancer Control (UICC, the 7th edition) guidelines for GMs.

Immunohistochemistry and mitosis findings

Paraffin-embedded tissue sections were immunostained using Histofine Simple Stain MAX PO (Nichirei) kits. After deparaffinization, endogenous peroxidase activity was blocked by incubating sections with 0.3% hydrogen peroxide in methanol for 30 min. Sections were incubated for 1 h at room temperature with an anti-CD8 antibody (713201; Nichirei), anti-PD-1 antibody (diluted 1:100, clone NAT105; ab52587; Abcam), anti-FOXp3 antibody (diluted 1:200, ab22510; Abcam), anti-BRAF V600E antibody (diluted 1:50, E19290; Spring Bioscience), HLA-DR-DP-DQ-DX, major histocompatibility complex class-II in melanomas (16) (diluted 1:1000, sc-53302; Santa Cruz Biotechnology, Inc.), and anti-PD-L1 antibody (diluted 1:100, clone 28-8; ab205921; Abcam). Bound antibodies were detected using diaminobenzidine tetrahydrochloride as a chromogen.

An immunohistochemical review was performed separately by two of the authors (MA and YM), who were blinded to clinical and outcome data. To evaluate the immunostaining results, any tumor cell showing the expression of PD-L1, BRAFV600E, or HLA was interpreted as positive. If none of the tumor cells expressed PD-L1, BRAFV600E, or HLA, the sample was negative. For the evaluation of CD8, PD-1, and FOXp3, the number of positive lymphocytes in the tumor area was scored as follows: 0, negative; <25%; 1+, low; 25–50%; 2+, intermediate; and >50% 3+, high. Scores of 0 and 1 were low, and scores of 2 and 3 were high.

Statistical analysis

Clinicopathological features were analyzed using χ2 tests and Student's t-tests. The level of significance was set to P<0.05 for all analyses. Statistical analyses were performed using StatViewJ version 5.0 (SAS Institute, Inc.).

Results

Comparison of SM and GM

The clinicopathological characteristics of patients with SM and GM are summarized in Table I. Consistent with our previous findings (7), patients with GM showed significantly higher proportions of lymph node and distant metastases than those of patients with SM (P=0.0448 and 0.0247, respectively).

Table I.

Clinicopathological characteristics of patients with melanoma of the skin and gastrointestinal tract.

Table I.

Clinicopathological characteristics of patients with melanoma of the skin and gastrointestinal tract.

VariableSkin, n (%)Gastrointestinal tract, n (%)P-value
Age, years (mean ± SD)66.7±16.875.7±14.90.1384
Sex
  Male17 (54.8)5 (50.0)0.7896
  Female14 (45.2)5 (50.0)
Location
  Acral/CSD/mucosal/non-CSD13/4/2/12 (41.9/12.9/6.5/38.7)
  Esophagus/rectum/anal canal/small intestine 1/4/4/1 (10.0/40.0/40.0/10.0)
T-classification
  1  8 (25.8)3 (30.0)0.0747
  211 (35.5)0 0.0
  311 (35.5)5 (50.0)
  4  1 (3.2)2 (20.0)
N-lymph node
  Negative21 (67.7)4 (40.0)0.0448a
  Positive10 (32.3)6 (60.0)
M-metastasis
  Negative30 (96.8)8 (80.0)0.0247a
  Positive  1 (3.2)2 (20.0)
UICC stage
  I  8 (25.8)3 (30.0)0.0747
  II11 (35.5)0 (0.0)
  III11 (35.5)5 (50.0)
  IV  1 (3.2)2 (20.0)
BRAFV600E
  Positive12 (38.7)1 (10.0)0.0898
  Negative19 (61.3)9 (90.0)
PD-L1
  Positive24 (77.4)9 (90.0)0.3827
  Negative  7 (22.6)1 (10.0)
HLA
  Positive10 (32.3)5 (50.0)0.3111
  Negative21 (67.7)5 (50.0)
CD8(+) lymphocyte
  High12 (25.8)8 (60.0)0.0231a
  Low19 (74.2)2 (40.0)
PD-1(+) lymphocyte
  High  7 (6.5)5 (30.0)0.0975
  Low24 (93.5)5 (70.0)
FOXp3(+) lymphocyte
  High26 (32.3)8 (22.2)0.7105
  Low  5 (67.7)1 (77.8)

a P<0.05, skin vs. gastrointestinal tract in c2 test. The number of FOXp3-GM cases was 9. The data are presented as the number of patients with percentages in the parentheses. The data for age are presented as the mean ± SD. CSD, chronic sun damaged; PD-1, programmed cell death protein 1; HLA, human leukocyte antigen; UICC, Union for International Cancer Control.

SM and GM showed PD-L1 and HLA expression in tumor cells (Fig. 1). As compared to SM, GM showed a higher proportion of PD-L1-positive cases (77.4 and 90.0%, respectively, Table I) and a higher proportion of HLA-positive cases (32.3 and 50.0%, respectively, Table I).

GM showed a significantly greater degree of infiltration of CD8+ lymphocytes than SM (P=0.0231, Table I and Fig. 2). As compared to SM, GM showed higher infiltration of PD-1+ lymphocytes, but this difference was not significant (P=0.0975). FOXp3+ lymphocytes did not differ between SM and GM.

Comparison of PD-L1-positive and -negative melanomas

We did not detect statistically significant differences between PD-L1-positive and -negative cases in SM or GM owing to the small sample sizes; therefore, we compared PD-L1-positive and -negative cases in both GM and SM. Patients with PD-L1-positive melanoma were younger than those with PD-L1-negative melanoma and were predominantly female (Table II). PD-L1-positive melanoma showed a higher proportion of BRAFV600E than that of PD-L1-negative melanoma (P=0.0317, 39.4 and 0%). PD-L1-positive melanomas showed significantly higher CD8+ or FOXp3+ lymphocyte infiltration than that of PD-L1-negative melanomas (P=0.0221 and P=0.0463, respectively). In contrast, PD-1+ lymphocytes did not differ between PD-L1-positive and -negative cases.

Table II.

Clinicopathological characteristics of patients with PD-L1-positive melanoma.

Table II.

Clinicopathological characteristics of patients with PD-L1-positive melanoma.

VariablesPD-L1 positive, n (%)PD-L1 negative, n (%)P-value
Age, years (mean ± SD)67.4±17.675.0±10.10.2520
Sex
  Male16 (48.4)6 (75.0)0.1677
  Female17 (51.5)2 (25.0)
Location of lesion
  SM24 (77.4)7 (22.6)0.3827
  GM  9 (90.0)1 (10.0)
UICC stage
  I  8 (24.2)3 (37.5)0.7054
  II  9 (27.3)1 (12.5)
  III14 (42.4)3 (37.5)
  IV  2 (6.1)1 (12.5)
BRAFV600E
  Positive13 (39.4)0 (0.0)0.0317a
  Negative20 (60.6)8 (100.0)
HLA
  Positive13 (39.4)2 (25.0)0.4483
  Negative20 (60.6)6 (75.0)
CD8(+) lymphocyte
  High19 (57.6)1 (12.5)0.0221a
  Low14 (42.4)7 (87.5)
PD-1(+) lymphocyte
  High10 (30.3)2 (25.0)0.7674
  Low23 (69.7)6 (75.0)
FOXp3(+) lymphocyte
  High29 (90.6)5 (62.5)0.0463a
  Low  3 (9.4)3 (37.5)

a P<0.05, PD-L1 positive vs. PD-L1 negative in c2 test. SM, skin melanoma; GM, gastrointestinal melanoma; PD-L1, programmed death ligand 1; PD-1, programmed cell death protein 1; HLA, human leukocyte antigen; UICC, Union for International Cancer Control.

Comparison of HLA-positive and -negative melanomas

We compared HLA-positive and -negative cases in both GM and SM. Patients with HLA-positive melanoma were older than patients with HLA-negative melanoma and were predominantly male (Table III). HLA-positive melanoma showed higher proportions of PD-1 (P=0.0101, 53.7 and 15.4%) and CD8 than those of HLA-negative melanoma (P=0.0818, 66.7 and 38.2%). In contrast, HLA+ lymphocytes did not differ between FOXp3, BRAFV600E, and PD-L1-positive and -negative cases.

Table III.

Clinicopathological characteristics of patients with HLA-positive melanoma.

Table III.

Clinicopathological characteristics of patients with HLA-positive melanoma.

VariablesHLA positive, n (%)HLA negative, n (%)P-value
Age, years (mean ± SD)72.5±15.966.8±17.00.3024
Sex
  Male  9 (60.0)13 (50.0)0.5362
  Female  6 (40.0)13 (50.0)
Location of lesion
  SM10 (32.3)21 (67.7)0.3111
  GM  5 (50.0)  5 (50.0)
UICC stage
  I  3 (20.0)  8 (30.8)0.6495
  II  4 (26.7)  6 (23.1)
  III  6 (40.0)11 (42.3)
  IV  2 (13.3)  1 (3.8)
BRAFV600E
  Positive  5 (33.3)  8 (30.8)0.8651
  Negative10 (66.7)18 (69.2)
PD-L1
  Positive13 (86.7)20 (76.9)0.4483
  Negative  2 (13.3)  6 (23.1)
CD8(+) lymphocyte
  High10 (66.7)10 (38.2)0.0818
  Low  5 (33.3)16 (61.5)
PD-1(+) lymphocyte
  High  8 (53.3)  4 (15.4)0.0101a
  Low  7 (46.7)22 (84.6)
FOXp3(+) lymphocyte
  High14 (93.3)20 (80.0)0.2529
  Low  1 (6.7)  5 (20.0)

a P<0.05, HLA positive vs. HLA negative in c2 test. SM, skin melanoma; GM, gastrointestinal melanoma; PD-L1, programmed death ligand 1; PD-1, programmed cell death protein 1; HLA, human leukocyte antigen; UICC, Union for International Cancer Control.

Discussion

We characterized the expression of immune-oncology markers in SM and GM. Compared with SM, GM exhibited greater degrees of infiltration of CD8+ and PD1-positive lymphocytes and higher levels of PD-L1 and HLA in melanoma cells. Furthermore, patients with PD-L1-positive melanoma were younger, female-predominant, and had a higher proportion of BRAFV600E positivity and a higher infiltration rate of CD8+ or FOXp3+ lymphocytes as compared to those of patients with PD-L1-negative melanomas. Patients with HLA-positive melanoma were older, male-predominant, and had higher infiltration of PD-1-positive lymphocytes as compared to those of patients with HLA-negative melanoma. These results indicate that GM shows greater activation of tumor immunity than SM, and thus GM might exhibit a greater response to ICIs.

Our results have several potential explanations. (1) GM cases represented a more advanced stage than that of SM cases owing to the difficulty of early diagnosis; therefore, advanced melanoma might induce the activation of tumor immunity depending on the disease duration. (2) GM tended to have higher incidences of PD-L1+ and HLA+ than those of SM; therefore, the characteristics of tumor cells might differ between GM and SM depending on tumor origin. (3) The tumor microenvironment must differ between GM and SM. Immune cells are more abundant in the gastrointestinal tract than in the skin.

Previously, we have reported that GMs were significantly more likely than SMs to be amelanotic and display round cells and aggressive features (lymph node and distant metastasis) (7). Further research should analyze the important differences in gene expression or response to therapy based on race and histological subtype, with a larger cohort of melanoma patients. However, we have not performed these analyses in the current study due to the small number of cases.

Patients with PD-L1-positive sarcoma are younger than those with PD-L1-negative sarcoma (17), as observed for melanoma in the present study. In contrast, patients with HLA-positive melanomas were older than those with HLA-negative melanomas in the present study. These results suggested that aging influences tumor immunity by decreasing tumor-specific memory T cells and increasing immune-suppressive cells (18). Different treatment strategies might be needed for elderly patients. Thus, older patients with melanoma reportedly responded better to ICI treatment than younger ones (19). Furthermore, it is important to consider the physical condition of elderly individuals when deciding to perform a surgical intervention. Therefore, ICI treatment may be recommended for the elderly.

Many studies have shown that the infiltration of CD8+ cytotoxic T cells plays key roles in the cancer-initiating cell (CIC) response (20), but the roles and clinical impact of FOXp3+ regulatory T cells on the CIC response are not fully understood (21). A previous report has shown that PD-L1 expression in SM (22,23), and all types of melanoma (24) is associated with CD8+ lymphocytes, consistent with our findings. Furthermore, PD-L1 expression is associated with FOXp3+ lymphocytes in sarcoma (17) and breast cancer (25), consistent with our results. CD8+ lymphocytes as well as PD-L1 expression in tumor cells might be candidate predictive biomarkers for the CIC response.

Previous studies have demonstrated PD-L1 expression on tumor cells using immunohistochemical staining for melanoma subtypes (24) and PD-L1 expression and copy number in primary vaginal melanomas utilizing fluorescence in situ hybridization (FISH) (26). The existence of differences between patients from Asia and other geographical areas is controversial (22,24,2628). Further studies, analyzing cohorts of individuals stratified by race and histological type are necessary to clarify the presence of differences in rare melanoma types.

Several companion assays are on the market to assess PD-L1 expression by immunohistochemistry, each of which is linked to a different drug. Tests for the expression of PD-L1 are not required for use of ICI in melanoma but may provide physicians and patients more information. PD-L1 expression in SM as detected by the PD-L1 clone 28-8 is correlated with the magnitude of the treatment effect of nivolumab with respect to progression-free survival (8). Our results suggest that PD-L1 28-8 testing is useful in GM.

Our study had a few limitations. Primarily, the number of cases was small, and most of the patients were elderly, especially in the GM group. Second, we examined the difference between regions but not the type of disease. Third, the quantification of expression levels depended solely on the histochemistry technique. Finally, the homogeneity of cases and heterogeneity of tissues might have affected the results.

In conclusion, our results provide useful information regarding tumor immunity in GM and SM. Further studies are needed to enable accurate predictions of the effect of immunotherapy.

Acknowledgements

The authors would like to thank Dr Seiichi Shinji (Surgery for Organ Function and Biological Regulation, Nippon Medical School, Tokyo, Japan) for his support in case presentations. The authors would also like to thank Ms. Yasuko Hasegawa (Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan) for her immunohistochemical work.

Funding

The present study was supported by a Grant-in-Aid for Young Scientists (B) (grant no. 15K19705 to MA).

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

MA, YM and HS were involved in the conception and design of the study. MA collected the data and performed the experiments. MA, YM and TA analyzed the data. MA and YM wrote the paper. TA and HS critically revised the manuscript. All authors read and approved the final version of the manuscript.

Ethics approval and consent to participate

Approval for the study was obtained from the Human Research Ethics Committees at the Tokyo Metropolitan Geriatric Hospital (approval no. R17-33) and the Nippon Medical School Hospital (approval no. 29-07-805). Written informed consent for the anonymous use of their data and tissue samples for study purposes was obtained from all patients.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Lee ML, Tomsu K and Von Eschen KB: Duration of survival for disseminated malignant melanoma: Results of a meta-analysis. Melanoma Res. 10:81–92. 2000.PubMed/NCBI

2 

Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit DG, Ding S, et al: Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 27:6199–6206. 2009. View Article : Google Scholar : PubMed/NCBI

3 

Baderca F, Vincze D, Balica N and Solovan C: Mucosal melanomas in the elderly: Challenging cases and review of the literature. Clin Interv Aging. 9:929–937. 2014. View Article : Google Scholar : PubMed/NCBI

4 

Chen H, Cai Y, Liu Y, He J, Hu Y, Xiao Q, Hu W and Ding K: Incidence, surgical treatment, and prognosis of anorectal melanoma from 1973 to 2011: A population-based SEER analysis. Medicine (Baltimore). 95:e27702016. View Article : Google Scholar : PubMed/NCBI

5 

Arai T, Yanagisawa A, Kondo F, Aida J and Takubo K: Clinicopathologic characteristics of esophageal primary malignant melanoma. Esophagus. 13:17–24. 2016. View Article : Google Scholar

6 

Cheung MC, Perez EA, Molina MA, Jin X, Gutierrez JC, Franceschi D, Livingstone AS and Koniaris LG: Defining the role of surgery for primary gastrointestinal tract melanoma. J Gastrointest Surg. 12:731–738. 2008. View Article : Google Scholar : PubMed/NCBI

7 

Akiyama M, Matsuda Y, Arai T and Saeki H: Clinicopathological characteristics of malignant melanomas of the skin and gastrointestinal tract. Oncol Lett. 16:2675–2681. 2018.PubMed/NCBI

8 

Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, et al: Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 16:375–384. 2015. View Article : Google Scholar : PubMed/NCBI

9 

Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, et al: Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 192:1027–1034. 2000. View Article : Google Scholar : PubMed/NCBI

10 

Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 366:2443–2454. 2012. View Article : Google Scholar : PubMed/NCBI

11 

Scheel AH, Dietel M, Heukamp LC, Jöhrens K, Kirchner T, Reu S, Rüschoff J, Schildhaus HU, Schirmacher P, Tiemann M, et al: Harmonized PD-L1 immunohistochemistry for pulmonary squamous-cell and adenocarcinomas. Mod Pathol. 29:1165–1172. 2016. View Article : Google Scholar : PubMed/NCBI

12 

Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, et al: Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 371:2189–2199. 2014. View Article : Google Scholar : PubMed/NCBI

13 

Gibney GT, Weiner LM and Atkins MB: Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 17:e542–e551. 2016. View Article : Google Scholar : PubMed/NCBI

14 

Hori S, Nomura T and Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science. 299:1057–1061. 2003. View Article : Google Scholar : PubMed/NCBI

15 

Chen DS and Mellman I: Elements of cancer immunity and the cancer-immune set point. Nature. 541:321–330. 2017. View Article : Google Scholar : PubMed/NCBI

16 

Johnson DB, Estrada MV, Salgado R, Sanchez V, Doxie DB, Opalenik SR, Vilgelm AE, Feld E, Johnson AS, Greenplate AR, et al: Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy. Nat Commun. 7:105822016. View Article : Google Scholar : PubMed/NCBI

17 

Que Y, Xiao W, Guan YX, Liang Y, Yan SM, Chen HY, Li QQ, Xu BS, Zhou ZW and Zhang X: PD-L1 expression is associated with FOXP3+ regulatory T-cell infiltration of soft tissue sarcoma and poor patient prognosis. J Cancer. 8:2018–2025. 2017. View Article : Google Scholar : PubMed/NCBI

18 

Pawelec G: Does patient age influence anti-cancer immunity? Semin Immunopathol. 41:125–131. 2019. View Article : Google Scholar : PubMed/NCBI

19 

Kugel CH III, Douglass SM, Webster MR, Kaur A, Liu Q, Yin X, Weiss SA, Darvishian F, Al-Rohil RN, Ndoye A, et al: Age correlates with response to anti-PD1, reflecting age-related differences in intratumoral effector and regulatory T-cell populations. Clin Cancer Res. 24:5347–5356. 2018. View Article : Google Scholar : PubMed/NCBI

20 

Espinosa E, Márquez-Rodas I, Soria A, Berrocal A, Manzano JL, Gonzalez-Cao M and Martin-Algarra S; Spanish Melanoma Group (GEM), : Predictive factors of response to immunotherapy-a review from the Spanish Melanoma Group (GEM). Ann Transl Med. 5:3892017. View Article : Google Scholar : PubMed/NCBI

21 

Shang B and Liu Y, Jiang SJ and Liu Y: Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: A systematic review and meta-analysis. Sci Rep. 5:151792015. View Article : Google Scholar : PubMed/NCBI

22 

Yun S, Park Y, Moon S, Ahn S, Lee K, Park HJ, Lee HS, Choe G and Lee KS: Clinicopathological and prognostic significance of programmed death ligand 1 expression in Korean melanoma patients. J Cancer. 10:3070–3078. 2019. View Article : Google Scholar : PubMed/NCBI

23 

Frydenlund N, Leone D, Yang S, Hoang MP, Deng A, Hernandez-Perez M, Singh R, Biswas A, Yaar R and Mahalingam M: Tumoral PD-L1 expression in desmoplastic melanoma is associated with depth of invasion, tumor-infiltrating CD8 cytotoxic lymphocytes and the mixed cytomorphological variant. Mod Pathol. 30:357–369. 2017. View Article : Google Scholar : PubMed/NCBI

24 

Kaunitz GJ, Cottrell TR, Lilo M, Muthappan V, Esandrio J, Berry S, Xu H, Ogurtsova A, Anders RA, Fischer AH, et al: Melanoma subtypes demonstrate distinct PD-L1 expression profiles. Lab Invest. 97:1063–1071. 2017. View Article : Google Scholar : PubMed/NCBI

25 

Li Z, Dong P, Ren M, Song Y, Qian X, Yang Y, Li S, Zhang X and Liu F: PD-L1 expression is associated with tumor FOXP3(+) regulatory T-cell infiltration of breast cancer and poor prognosis of patient. J Cancer. 7:784–793. 2016. View Article : Google Scholar : PubMed/NCBI

26 

Wang HY, Wu XY, Zhang X, Yang XH, Long YK, Feng YF and Wang F: Prevalence of NRAS mutation, PD-L1 expression and amplification, and overall survival analysis in 36 primary vaginal melanomas. Oncologist. Oct 2–2019.(Epub ahead of print). doi: 10.1634/theoncologist2019-0148. View Article : Google Scholar

27 

Koelblinger P, Emberger M, Drach M, Cheng PF, Lang R, Levesque MP, Bauer JW and Dummer R: Increased tumour cell PD-L1 expression, macrophage and dendritic cell infiltration characterise the tumour microenvironment of ulcerated primary melanomas. J Eur Acad Dermatol Venereol. 33:667–675. 2019. View Article : Google Scholar : PubMed/NCBI

28 

Thierauf J, Veit JA, Affolter A, Bergmann C, Grünow J, Laban S, Lennerz JK, Grünmüller L, Mauch C, Plinkert PK, et al: Identification and clinical relevance of PD-L1 expression in primary mucosal malignant melanoma of the head and neck. Melanoma Res. 25:503–509. 2015. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

March-2020
Volume 19 Issue 3

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Akiyama M, Matsuda Y, Arai T and Saeki H: PD‑L1 expression in malignant melanomas of the skin and gastrointestinal tract. Oncol Lett 19: 2481-2488, 2020
APA
Akiyama, M., Matsuda, Y., Arai, T., & Saeki, H. (2020). PD‑L1 expression in malignant melanomas of the skin and gastrointestinal tract. Oncology Letters, 19, 2481-2488. https://doi.org/10.3892/ol.2020.11325
MLA
Akiyama, M., Matsuda, Y., Arai, T., Saeki, H."PD‑L1 expression in malignant melanomas of the skin and gastrointestinal tract". Oncology Letters 19.3 (2020): 2481-2488.
Chicago
Akiyama, M., Matsuda, Y., Arai, T., Saeki, H."PD‑L1 expression in malignant melanomas of the skin and gastrointestinal tract". Oncology Letters 19, no. 3 (2020): 2481-2488. https://doi.org/10.3892/ol.2020.11325