TY - JOUR
T1 - B7-H3 expression in Merkel cell carcinoma–associated endothelial cells correlates with locally aggressive primary tumor features and increased vascular density
AU - Aung, Phyu P.
AU - Parra, Edwin Roger
AU - Barua, Souptik
AU - Sui, Dawen
AU - Ning, Jing
AU - Mino, Barbara
AU - Ledesma, Debora Alejandra
AU - Curry, Jonathan L.
AU - Nagarajan, Priyadharsini
AU - Torres-Cabala, Carlos A.
AU - Efstathiou, Eleni
AU - Hoang, Anh G.
AU - Wong, Michael K.
AU - Wargo, Jennifer A.
AU - Lazar, Alexander J.
AU - Rao, Arvind
AU - Prieto, Victor G.
AU - Wistuba, Ignacio
AU - Tetzlaff, Michael T.
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy whose pathogenesis and prognosis are related to the integrity of the host immune system. Despite promising clinical responses to immune-checkpoint blockade, response and resistance remain unpredictable, underscoring a critical need to delineate novel prognostic biomarkers and/or therapeutic targets for this disease. Experimental Design: Expression of immune-regulatory markers (PD-L2, B7-H3, B7-H4, IDO-1, ICOS, TIM3, LAG3, VISTA, and OX-40) was assessed using singlet chromogenic IHC in 10 primary MCCs. Multiplex immunofluorescence quantified CD31 and B7-H3 expression in 52 primary and 25 metastatic MCCs. B7-H3 and CD31 expressions were tabulated as a series of independent (X,Y) cell centroids. A spatial G-function, calculated based on the distribution of distances of B7-H3þ (X,Y) cell centroids around the CD31þ (X,Y) cell centroids, was used to estimate a colocalization index equivalent to the percentage of CD31-positive cell centroids that overlap with a B7-H3–positive cell centroid. Results: Primary and metastatic MCCs exhibit a dynamic range of colocalized CD31 and B7-H3 expression. Increasing colocalized expression of B7-H3 with CD31 significantly associated with increased tumor size (P ¼ 0.0060), greater depth of invasion (P ¼ 0.0110), presence of lymphovascular invasion (P ¼ 0.0453), and invasion beyond skin (P ¼ 0.0428) in primary MCC. Consistent with these findings, increasing colocalized expression of B7-H3 and CD31 correlated with increasing vascular density in primary MCC, but not metastatic MCC. Conclusions: Our results demonstrate that colocalized expression of B7-H3/CD31 is a poor prognostic indicator and suggest therapies targeting B7-H3 may represent an effective approach to augmenting immune-activating therapies for MCC.
AB - Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy whose pathogenesis and prognosis are related to the integrity of the host immune system. Despite promising clinical responses to immune-checkpoint blockade, response and resistance remain unpredictable, underscoring a critical need to delineate novel prognostic biomarkers and/or therapeutic targets for this disease. Experimental Design: Expression of immune-regulatory markers (PD-L2, B7-H3, B7-H4, IDO-1, ICOS, TIM3, LAG3, VISTA, and OX-40) was assessed using singlet chromogenic IHC in 10 primary MCCs. Multiplex immunofluorescence quantified CD31 and B7-H3 expression in 52 primary and 25 metastatic MCCs. B7-H3 and CD31 expressions were tabulated as a series of independent (X,Y) cell centroids. A spatial G-function, calculated based on the distribution of distances of B7-H3þ (X,Y) cell centroids around the CD31þ (X,Y) cell centroids, was used to estimate a colocalization index equivalent to the percentage of CD31-positive cell centroids that overlap with a B7-H3–positive cell centroid. Results: Primary and metastatic MCCs exhibit a dynamic range of colocalized CD31 and B7-H3 expression. Increasing colocalized expression of B7-H3 with CD31 significantly associated with increased tumor size (P ¼ 0.0060), greater depth of invasion (P ¼ 0.0110), presence of lymphovascular invasion (P ¼ 0.0453), and invasion beyond skin (P ¼ 0.0428) in primary MCC. Consistent with these findings, increasing colocalized expression of B7-H3 and CD31 correlated with increasing vascular density in primary MCC, but not metastatic MCC. Conclusions: Our results demonstrate that colocalized expression of B7-H3/CD31 is a poor prognostic indicator and suggest therapies targeting B7-H3 may represent an effective approach to augmenting immune-activating therapies for MCC.
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U2 - 10.1158/1078-0432.CCR-18-2355
DO - 10.1158/1078-0432.CCR-18-2355
M3 - Article
C2 - 30808776
AN - SCOPUS:85066611708
SN - 1078-0432
VL - 25
SP - 3455
EP - 3467
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 11
ER -