TY - JOUR
T1 - Melanoma subtypes demonstrate distinct PD-L1 expression profiles
AU - Kaunitz, Genevieve J.
AU - Cottrell, Tricia R.
AU - Lilo, Mohammed
AU - Muthappan, Valliammai
AU - Esandrio, Jessica
AU - Berry, Sneha
AU - Xu, Haiying
AU - Ogurtsova, Aleksandra
AU - Anders, Robert A.
AU - Fischer, Alexander H.
AU - Kraft, Stefan
AU - Gerstenblith, Meg R.
AU - Thompson, Cheryl L.
AU - Honda, Kord
AU - Cuda, Jonathan D.
AU - Eberhart, Charles G.
AU - Handa, James T.
AU - Lipson, Evan J.
AU - Taube, Janis M.
N1 - Funding Information:
We thank Dr Suzanne L. Topalian (Johns Hopkins University School of Medicine) for critical review of the manuscript. This work was supported by the Dermatology Foundation (JMT, MRG); the Melanoma Research Alliance (JMT); Bristol-Myers Squibb (JMT, RAA); Sidney Kimmel Cancer Center Core Grant P30 CA006973 (JMT, EJL); the National Cancer Institute NIH Grant R01 CA142779 (JMT); NIH Grant T32 CA193145 (TRC); unrestricted grant from Research to Prevent Blindness (Wilmer Eye Institute) (JTH); Moving for Melanoma of Delaware (JMT, EJL); and the Char and Chuck Fowler Family Foundation (MRG, CLT). We were also supported by the Bloomberg Kimmel Institute for Cancer Immunotherapy and a Stand Up To Cancer-Cancer Research Institute Cancer Immunology Translational Cancer Research Grant (SU2C-AACR-DT1012). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research.
Publisher Copyright:
© 2017 USCAP, Inc.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - PD-L1 expression in the tumor immune microenvironment is recognized as both a prognostic and predictive biomarker in patients with cutaneous melanoma, a finding closely related to its adaptive (IFN-Î 3-mediated) mechanism of expression. Approximately 35% of cutaneous melanomas express PD-L1, however, the expression patterns, levels, and prevalence in rarer melanoma subtypes are not well described. We performed immunohistochemistry for PD-L1 and CD8 on 200 formalin-fixed paraffin-embedded specimens from patients with acral (n=16), mucosal (n=36), uveal (n=103), and chronic sun-damaged (CSD) (n=45) melanomas (24 lentigo maligna, 13 â mixed' desmoplastic, and 8 â pure' desmoplastic melanomas). CD8+ tumor-infiltrating lymphocyte (TIL) densities were characterized as mild, moderate, or severe, and their geographic association with PD-L1 expression was evaluated. Discrete lymphoid aggregates, the presence of a spindle cell morphology, and the relationship of these features with PD-L1 expression were assessed. PD-L1 expression was observed in 31% of acral melanomas, 44% of mucosal melanomas, 10% of uveal melanomas, and 62% of CSD melanomas (P<0.0001). Compared to our previously characterized cohort of cutaneous melanomas, the proportion of PD-L1(+) tumors was lower in uveal (P=0.0002) and higher in CSD (P=0.0073) melanomas, while PD-L1 expression in the acral and mucosal subtypes was on par. PD-L1 expression in all subtypes correlated with a moderate-severe grade of CD8+ TIL (all, P<0.003), supporting an adaptive mechanism of expression induced during the host antitumor response. The tumor microenvironments observed in CSD melanomas segregated by whether they were the pure desmoplastic subtype, which showed lower levels of PD-L1 expression when compared to other CSD melanomas (P=0.047). The presence of lymphoid aggregates was not associated with the level of PD-L1 expression, while PD-L1(+) cases with spindle cell morphology demonstrated higher levels of PD-L1 than those with a nested phenotype (P<0.0001). Our findings may underpin the reported clinical response rates for anti-PD-1 monotherapy, which vary by subtype.
AB - PD-L1 expression in the tumor immune microenvironment is recognized as both a prognostic and predictive biomarker in patients with cutaneous melanoma, a finding closely related to its adaptive (IFN-Î 3-mediated) mechanism of expression. Approximately 35% of cutaneous melanomas express PD-L1, however, the expression patterns, levels, and prevalence in rarer melanoma subtypes are not well described. We performed immunohistochemistry for PD-L1 and CD8 on 200 formalin-fixed paraffin-embedded specimens from patients with acral (n=16), mucosal (n=36), uveal (n=103), and chronic sun-damaged (CSD) (n=45) melanomas (24 lentigo maligna, 13 â mixed' desmoplastic, and 8 â pure' desmoplastic melanomas). CD8+ tumor-infiltrating lymphocyte (TIL) densities were characterized as mild, moderate, or severe, and their geographic association with PD-L1 expression was evaluated. Discrete lymphoid aggregates, the presence of a spindle cell morphology, and the relationship of these features with PD-L1 expression were assessed. PD-L1 expression was observed in 31% of acral melanomas, 44% of mucosal melanomas, 10% of uveal melanomas, and 62% of CSD melanomas (P<0.0001). Compared to our previously characterized cohort of cutaneous melanomas, the proportion of PD-L1(+) tumors was lower in uveal (P=0.0002) and higher in CSD (P=0.0073) melanomas, while PD-L1 expression in the acral and mucosal subtypes was on par. PD-L1 expression in all subtypes correlated with a moderate-severe grade of CD8+ TIL (all, P<0.003), supporting an adaptive mechanism of expression induced during the host antitumor response. The tumor microenvironments observed in CSD melanomas segregated by whether they were the pure desmoplastic subtype, which showed lower levels of PD-L1 expression when compared to other CSD melanomas (P=0.047). The presence of lymphoid aggregates was not associated with the level of PD-L1 expression, while PD-L1(+) cases with spindle cell morphology demonstrated higher levels of PD-L1 than those with a nested phenotype (P<0.0001). Our findings may underpin the reported clinical response rates for anti-PD-1 monotherapy, which vary by subtype.
UR - http://www.scopus.com/inward/record.url?scp=85028511052&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85028511052&partnerID=8YFLogxK
U2 - 10.1038/labinvest.2017.64
DO - 10.1038/labinvest.2017.64
M3 - Article
C2 - 28737763
AN - SCOPUS:85028511052
SN - 0023-6837
VL - 97
SP - 1063
EP - 1071
JO - Laboratory Investigation
JF - Laboratory Investigation
IS - 9
ER -