HLA Class I Antigen Expression in Conjunctival Melanoma Is Not Associated With PD-L1/PD-1 Status

Cao, Jinfeng; Brouwer, Niels J.; Jordanova, Ekaterina S.; Marinković, Marina; Duinen, Sjoerd G. van; Waard, Nadine E de; Ksander, Bruce R.; Mulder, Arend; Claas, Frans H.J.; Heemskerk, Mirjam H.M.; Jager, Martine J.

doi:10.1167/iovs.17-23209

Cited by 11 publications

(6 citation statements)

References 50 publications

(59 reference statements)

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“…Although MHC class I loss has been reported in several types of tumors ranging from 15% to 96% 12,13,18,19 , few studies have assessed the proportion of concomitant expression of MHC class I and PD-L1, whereas some have analyzed a single parameter’s expression and relation with immune cell infiltration only 20–22 . Our data suggested that the frequency of MHC class I loss with concurrent PD-L1 expression was approximately 7.0% in our tissue microarray cohort, which is similar to 7% in non-small cell lung cancer 23 and 4.3% in conjunctival melanoma 24 . However, the prevalence is higher in esophageal squamous cell carcinoma (12.2%) 25 , non-small cell lung cancer (17%) 26 , and hepatocellular carcinoma (17%) 27 .…”

Section: Discussionsupporting

confidence: 72%

Prognostic value of the association between MHC class I downregulation and PD-L1 upregulation in head and neck squamous cell carcinoma patients

Yoo

Keam

Ock

et al. 2019

Sci Rep

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The purpose of this study was to evaluate the prognostic impact of major histocompatibility complex (MHC) class I expression and programmed death-ligand 1 (PD-L1) expression in patients with head and neck squamous cell carcinoma (HNSCC). A total of 158 patients with HNSCC were evaluated retrospectively. The expression of MHC class I and PD-L1 was analyzed in tumor specimens using immunohistochemistry. The association between MHC class I/PD-L1 expression and clinical outcome was evaluated by Kaplan-Meier and Cox regression analyses. Among 158 patients, 103 (65.2%) showed positive PD-L1 expression, and 20 (12.7%) showed no detectable expression of MHC class I. The frequency of PD-L1 positive expression with concomitant MHC class I loss was 7.0%. In the PD-L1-positive group, MHC class I loss was associated with a significantly worse survival compared with MHC class I positivity (median overall survival 39.3 months vs. not reached; P = 0.005), whereas MHC class I status provided no prognostic impact in the PD-L1 negative group. Neither PD-L1 nor MHC class I alone showed a significant difference in overall survival. The loss of MHC class I expression in PD-L1-positive HNSCC was associated with a poor clinical outcome. This suggested that MHC class I expression status might be useful for the prognosis of tumor progression in HNSCC when combined with PD-L1 expression status. External validation with enough numbers of participants in such subgroup should be needed for validation.

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Section: Discussionsupporting

confidence: 72%

Prognostic value of the association between MHC class I downregulation and PD-L1 upregulation in head and neck squamous cell carcinoma patients

Yoo

Keam

Ock

et al. 2019

Sci Rep

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“…Regarding innate and adaptive immune cells, no clear conclusion can be drawn because of the contradictory results regarding the role of tumour infiltrate lymphocytes (TILs) and tumour-associated macrophages (TAMs) [ 36 , 37 , 38 , 39 , 40 , 41 ]. Elevated levels of HLA Class I are associated with more TILs and TAMs and the expression of PD-L1 in CM seems almost similar to that found in cutaneous melanoma, even if lower percentages of expression levels have been reported [ 41 , 42 , 43 ]. The relevance of this predictive effect may be limited because, as with cutaneous melanoma, CMs with high PD-L1 levels have been shown to respond to PD-1 inhibitors [ 44 ].…”

Section: Biology Of Conjunctival Melanomamentioning

confidence: 63%

Small but Challenging Conjunctival Melanoma: New Insights, Paradigms and Future Perspectives

Nahon-Estève

Bertolotto

Picard‐Gauci

et al. 2021

Cancers

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Although its incidence has increased over the last decades, conjunctival melanoma (CM) remains a rare but challenging periocular malignancy. While there is currently no recognized standard of care, “no-touch” surgical excision followed by adjuvant treatments is usually recommended. Despite its small size, managing CM is challenging for clinicians. The first challenge is the high risk of tumour local recurrence that occurs in about one third of the patients. The management of locally advanced CM (≥T2) or multiple recurrences may require mutilating surgeries such as orbital exenteration (OE). The second challenge is the metastatic spread of CM that occurs in about one quarter of patients, regardless of whether complete surgical excision is performed or not. This highlights the infiltrative and highly aggressive behaviour of CM. Recently, attention has been directed towards the use of eye-sparing strategies to avoid OE. Initially, wide conservative surgeries followed by customized brachytherapy or radiotherapy have appeared as viable strategies. Nowadays, new biological insights into CM have revealed similarities with cutaneous melanoma. These new findings have allowed clinicians to reconsider the management of locally advanced CM with “medical” eye-sparing treatment as well as the management of metastatic spread. The aim of this review was to summarize the current and future perspectives of treatment for CM based on recent biological findings.

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“…In some malignancies, both “soft” (reversible) and “hard” (irreversible) downregulation of HLA-I may limit effective T cell immune responses. 51 , 52 Interestingly, reduced HLA-I expression is very common in melanoma prior to immune checkpoint therapy and associated with primary resistance to ipilimumab, but not to nivolumab. 51 In metastatic melanoma patients, regression of metastasis after immunotherapy is associated with the expression of HLA-I APM components and IFN-regulated rejections genes.…”

Section: Discussionmentioning

confidence: 99%

Identification of miR-200a-5p targeting the peptide transporter TAP1 and its association with the clinical outcome of melanoma patients

et al. 2020

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Tumor escape is often associated with abnormalities in the surface expression of the human leukocyte antigen class I (HLA-I) antigens thereby limiting CD8 + cytotoxic T cell responses. This impaired HLA-I surface expression can be mediated by deficient expression of components of the antigen processing and presentation machinery (APM) due to epigenetic, transcriptional and/or post-transcriptional processes. Since a discordant mRNA and protein expression pattern of APM components including the peptide transporter associated with antigen processing 1 (TAP1) has been frequently described in tumors of distinct origin, a post-transcriptional control of APM components caused by microRNAs (miR) was suggested. Using an in silico approach, miR-200a-5p has been identified as a candidate miR binding to the 3ʹ untranslated region (UTR) of TAP1. Luciferase reporter assays demonstrated a specific binding of miR-200a-5p to the TAP1 3ʹ-UTR. Furthermore, the miR-200a-5p expression is inversely correlated with the TAP1 protein expression in HEK293T cells and in a panel of melanoma cell lines as well as in primary melanoma lesions. High levels of miR-200a-5p expression were associated with a shorter overall survival of melanoma patients. Overexpression of miR-200a-5p reduced TAP1 levels, which was accompanied by a decreased HLA-I surface expression and an enhanced NK cell sensitivity of melanoma cells. These data show for the first time a miRmediated control of the peptide transporter subunit TAP1 in melanoma thereby leading to a reduced HLA-I surface expression accompanied by an altered immune recognition and reduced patients' survival.

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HLA Class I Antigen Expression in Conjunctival Melanoma Is Not Associated With PD-L1/PD-1 Status

Abstract: Our data indicate that subsets of CM have positive HLA class I expression, and HLA class I and PD-L1/PD-1 are expressed independently. When one considers immunotherapy, one should also analyze HLA class I expression, whose downregulation can limit the efficacy of T cell-mediated therapies.

Cited by 11 publications

References 50 publications

Prognostic value of the association between MHC class I downregulation and PD-L1 upregulation in head and neck squamous cell carcinoma patients

Prognostic value of the association between MHC class I downregulation and PD-L1 upregulation in head and neck squamous cell carcinoma patients

Small but Challenging Conjunctival Melanoma: New Insights, Paradigms and Future Perspectives

Identification of miR-200a-5p targeting the peptide transporter TAP1 and its association with the clinical outcome of melanoma patients

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