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Increased tumour cell PD-L1 expression, macrophage and dendritic cell infiltration characterise the tumour microenvironment of ulcerated primary melanomas


Koelblinger, P; Emberger, M; Drach, M; Cheng, PF; Lang, R; Levesque, MP; Bauer, JW; Dummer, R (2019). Increased tumour cell PD-L1 expression, macrophage and dendritic cell infiltration characterise the tumour microenvironment of ulcerated primary melanomas. Journal of the European Academy of Dermatology and Venerology, 33(4):667-675.

Abstract

BACKGROUND:

Primary melanoma ulceration is an unfavourable prognostic factor included in current staging systems. Yet, the immunological and molecular alterations responsible for this adverse outcome have not been fully elucidated.

OBJECTIVES:

We aimed to identify immunological differences between ulcerated and non-ulcerated primary melanomas concerning both innate and adaptive immunity and to correlate these with clinical outcome.

METHODS:

Formalin-fixed paraffin-embedded primary melanomas from 112 patients (pts) were analysed by immunohistochemistry. The expression of various markers identifying tumour-infiltrating lymphocytes, macrophages and dendritic cells was evaluated semi-quantitatively by three independent investigators. Tumour-cell expression of programmed-death ligand 1 (PD-L1), transporter of antigen-processing 1 and the MxA protein was also analysed.

RESULTS:

Recurrence occurred in 21/56 pts (37.5%) with ulcerated vs. 14/56 pts (25.0%) with non-ulcerated tumours (p=0.15). Tumour ulceration was associated with more frequent development of brain metastasis (17.6 versus 3.6% of pts, p =0.015). Immunohistochemistry showed an association of ulceration with the presence of intratumoural CD68+ macrophages (p=0.028) as well as with increased numbers of intratumoural CD11c+ dendritic cells (p=0.014) and CD163+ macrophages (p=0.001). PD-L1 positivity (expression in >1% of tumour cells) was more frequent in ulcerated than non-ulcerated tumours (40 (72.7%) vs. 25 (44.6%), p=0.003). A positive correlation between intratumoural CD11c+ (Spearman's correlation coefficient ρ: 0.42) and CD163+ (ρ: 0.31) cell count and frequency of tumour cell PD-L1 expression was detected.

CONCLUSIONS:

Our results confirm the adverse clinical outcome associated with primary melanoma ulceration, particularly concerning the risk of recurrence and subsequent development of brain metastases. The observed immunological differences suggest a conceivable role of increased intratumoural macrophage and dendritic cell counts associated with enhanced tumour cell PD-L1 expression potentially contributing to the immunosuppressive, growth-promoting microenvironment of ulcerated primary melanomas.

Abstract

BACKGROUND:

Primary melanoma ulceration is an unfavourable prognostic factor included in current staging systems. Yet, the immunological and molecular alterations responsible for this adverse outcome have not been fully elucidated.

OBJECTIVES:

We aimed to identify immunological differences between ulcerated and non-ulcerated primary melanomas concerning both innate and adaptive immunity and to correlate these with clinical outcome.

METHODS:

Formalin-fixed paraffin-embedded primary melanomas from 112 patients (pts) were analysed by immunohistochemistry. The expression of various markers identifying tumour-infiltrating lymphocytes, macrophages and dendritic cells was evaluated semi-quantitatively by three independent investigators. Tumour-cell expression of programmed-death ligand 1 (PD-L1), transporter of antigen-processing 1 and the MxA protein was also analysed.

RESULTS:

Recurrence occurred in 21/56 pts (37.5%) with ulcerated vs. 14/56 pts (25.0%) with non-ulcerated tumours (p=0.15). Tumour ulceration was associated with more frequent development of brain metastasis (17.6 versus 3.6% of pts, p =0.015). Immunohistochemistry showed an association of ulceration with the presence of intratumoural CD68+ macrophages (p=0.028) as well as with increased numbers of intratumoural CD11c+ dendritic cells (p=0.014) and CD163+ macrophages (p=0.001). PD-L1 positivity (expression in >1% of tumour cells) was more frequent in ulcerated than non-ulcerated tumours (40 (72.7%) vs. 25 (44.6%), p=0.003). A positive correlation between intratumoural CD11c+ (Spearman's correlation coefficient ρ: 0.42) and CD163+ (ρ: 0.31) cell count and frequency of tumour cell PD-L1 expression was detected.

CONCLUSIONS:

Our results confirm the adverse clinical outcome associated with primary melanoma ulceration, particularly concerning the risk of recurrence and subsequent development of brain metastases. The observed immunological differences suggest a conceivable role of increased intratumoural macrophage and dendritic cell counts associated with enhanced tumour cell PD-L1 expression potentially contributing to the immunosuppressive, growth-promoting microenvironment of ulcerated primary melanomas.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Infectious Diseases, Dermatology
Language:English
Date:1 April 2019
Deposited On:27 Nov 2018 10:28
Last Modified:30 Mar 2019 02:02
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0926-9959
OA Status:Closed
Publisher DOI:https://doi.org/10.1111/jdv.15302
PubMed ID:30357969

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