<scp>PD</scp>‐L1 expression in melanoma shows marked heterogeneity within and between patients: implications for anti‐<scp>PD</scp>‐1/<scp>PD</scp>‐<scp>L</scp>1 clinical trials

Madore, Jason; Vilain, Ricardo E.; Menzies, Alexander M.; Kakavand, Hojabr; Wilmott, James S.; Hyman, Jessica; Yearley, Jennifer H.; Kefford, Richard; Thompson, John F.; Long, Georgina V.; Hersey, Peter; Scolyer, Richard A.

doi:10.1111/pcmr.12340

Cited by 357 publications

(262 citation statements)

References 24 publications

(32 reference statements)

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“…26 In our cohort of patients, the expression of tumor PD-L1 correlated highly with the presence of intratumoral lymphocyte subsets, including those that were PD-1 positive. These results support previously reported findings by our group and others, 25,26,29 which suggest the presence of lymphocytes that secrete IFN-γ, as well as other co-contributing factors, drives the expression of tumor PD-L1 in an acquired adaptive immune evasion phenomenon. This model is also supported by our finding that patients with positive tumor PD-L1 have a higher median diameter of tumor in their sentinel lymph node compared to patients with tumors that were negative for PD-L1.…”

Section: Discussionsupporting

confidence: 82%

“…The membranous expression of tumor PD-L1 is heterogeneous both within any given melanoma and between various samples from the same patient. [29][30][31] Despite this evidence, tumoral PD-L1 expression had been demonstrated to be predictive of response to anti-PD-1 inhibitors. 32,33 Nevertheless, recent studies have shown that some patients with 'negative' PD-L1 expression still have objective responses to anti-PD-1 inhibitors 32 and anti-PD-L1 inhibitors; 34 therefore, reportedly absent PD-L1 expression cannot be used to exclude patients from this form of therapy.…”

Section: Discussionmentioning

confidence: 99%

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Tumor PD-L1 expression, immune cell correlates and PD-1+ lymphocytes in sentinel lymph node melanoma metastases

et al. 2015

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Melanoma patients with sentinel lymph node metastases have variable 5-year survival rates (39-70%). The prognostic significance of tumor-infiltrating lymphocytes in sentinel lymph node metastases from such patients is currently unknown. Anti-PD-1/PD-L1 inhibitors have significantly improved clinical outcome in unresectable AJCC stage IIIC/IV metastatic melanoma patients, and are being trialed in the adjuvant setting in advanced stage disease, however, their role in early stage (sentinel lymph node positive) metastatic disease remains unclear. The aims of this study were to characterize, in sentinel lymph nodes, the subpopulations of lymphocytes that interact with metastatic melanoma cells and analyze their associations with outcome, and to determine tumor PD-L1 expression as this may provide a rational scientific basis for the administration of adjuvant anti-PD-1/PD-L1 inhibitors in sentinel lymph node positive metastatic melanoma patients. Sentinel lymph nodes containing metastatic melanoma from 60 treatment-naive patients were analyzed for CD3, CD4, CD8, FOXP3, PD-1, and PD-L1 using immunohistochemistry on serial sections. The results were correlated with clinicopathologic features and outcome. Positive correlations between recurrence-free/overall survival with the number of CD3+ tumorinfiltrating lymphocytes (hazard ratio = 0.36 (0.17-0.76), P = 0.005; hazard ratio = 0.29 (0.14-0.61), P = 0.0005, respectively), the number of CD4+ tumor-infiltrating lymphocytes (hazard ratio = 0.34 (0.15-0.77), P = 0.007; hazard ratio = 0.32 (0.14-0.74), P = 0.005, respectively), and the number of CD8+ tumor-infiltrating lymphocytes (hazard ratio = 0.42 (0.21-0.85), P = 0.013; hazard ratio = 0.32 (0.19-0.78), P = 0.006, respectively) were observed. There was also a negative correlation with the number of peritumoral PD-1+ lymphocytes (hazard ratio = 2.67 (1.17-6.13), P = 0.016; hazard ratio = 2.74 (1.14-6.76), P = 0.019, respectively). Tumoral PD-L1 expression was present in 26 cases (43%) but did not correlate with outcome. The findings suggest that T-cell subsets in sentinel lymph node metastases can predict melanoma patient outcome. In addition, the relatively high number of PD-L1 positive sentinel lymph node melanoma metastases provides a rationale for anti-PD-1 therapy trials in sentinel lymph node positive melanoma patients, particularly those with peritumoral PD-1+ lymphocytes.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Tumor PD-L1 expression, immune cell correlates and PD-1+ lymphocytes in sentinel lymph node melanoma metastases

et al. 2015

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“…Others have reported discordance of PD-L1 expression among primary melanomas and their metastases (across a 1% threshold of positivity) in 50% of patients. 70 Notably, however, review of the data for that report reveals that 11 of the patients reported to have heterogeneous PD-L1 expression had values confined to the range of 0-5%, leaving 13/46 (28%) with heterogeneity across a 5% cutoff. Thus, heterogeneity rates may differ with different thresholds of positivity.…”

Section: Discussionmentioning

confidence: 99%

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

et al. 2016

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Therapeutic blockade of PD-1/PD-L1 can have dramatic therapeutic benefit in some patients; however, the prognostic associations of PD-1 and its ligands, in the absence of therapeutic blockade have not been definitively addressed. In particular, associations of PD-L2 with immune infiltrates and with outcome have yet to be explored. We hypothesized that surface expression of both PD-L1 and PD-L2 by melanoma cells would be associated with immune cell infiltration and with overall patient survival, independent of checkpoint blockade therapy. We also characterized the heterogeneity of their distribution within a tumor and within tumors of the same patient. Tissue microarrays of metastatic melanoma samples from 147 patients were quantified for CD8 C , CD45, CD4 C , CD3, CD163, CD20, CD138, FoxP3, PD-1, PD-L1 and PD-L2 markers by immunohistochemistry. Relationships between the proportions of PD-L1 and PD-L2 expressing tumor cells with the immune cell count, distribution (immunotype) and patient survival were studied. Expressions of both PD-L1 and PD-L2 correlated significantly with increasing densities of immune cells in the tumor specimens and with immunotype. Positive PD-L2 expression was associated with improved overall survival and the simultaneous positive expression of both PD-1 ligands showed a higher association with survival. Significant heterogeneity of PD-L1 and PD-L2 expressions within tumors were observed, however, they were less pronounced with PD-L2. In conclusion, both are markers of immune infiltration and PD-L2, alone or in combination with PD-L1, is a marker for prognosis in metastatic melanoma patients. Larger tumor samples yield more reliable assessments of PD-L1/L2 expression.

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“…[1][2][3][4] Studies from our group and others indicate that the major mechanism driving melanoma tumor cell PD-L1 expression is an association with tumor-infiltrating lymphocytes (TIL), consistent with an endogenous antitumor immune response that may be unleashed with anti-PD-1/PD-L1 therapies. 5 Such adaptive PD-L1 expression by melanoma is not dependent on BRAF, NRAS, or c-KIT mutational status.…”

mentioning

confidence: 99%

“…Discordance exists in PD-L1 expression between primary and metastatic lesions from the same patient as a result of the focal and dynamic nature of this biomarker. 3,13,19 Many of the early clinical trials that studied the relationship between PD-L1 expression in the pretreatment TME and response to anti-PD-1 did not specifically require an immediate pretreatment sample from a metastasis for the assessment of PD-L1 status. In a number of cases, primary melanomas or archival samples from metastases taken years prior to treatment were assayed.…”

mentioning

confidence: 99%

781 Melanoma subtypes demonstrate distinct PD-L1 expression profiles

Kaunitz¹,

Cottrell²,

Lilo³

et al. 2017

Journal of Investigative Dermatology

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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-γ-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, 13Correspondence: Dr JM Taube, MD, Division of Dermatopathology, Johns Hopkins Hospital, Blalock 907, 600N. Wolfe Street, Baltimore, MD 21287, USA. jtaube1@jhmi.edu. CONFLICT OF INTEREST:The remaining authors declare no conflict of interest. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript 'mixed' desmoplastic, and 8 '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.Increased objective response rates (ORRs) to anti-PD-1/PD-L1 monotherapy as well as improved progression-free survival and overall survival have been linked to PD-L1 expression in the tumor microenvironment (TME) in some studies. [1][2][3][4] Studies from our group and others indicate that the major mechanism driving melanoma tumor cell PD-L1 expression is an association with tumor-infiltrating lymphocytes (TIL), consistent with an endogenous antitumor immune response that may be unleashed with anti-PD-1/PD-L1 therapies. 5 Such adaptive PD-L1 expression by melanoma is...

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PD‐L1 expression in melanoma shows marked heterogeneity within and between patients: implications for anti‐PD‐1/PD‐L1 clinical trials

Cited by 357 publications

References 24 publications

Tumor PD-L1 expression, immune cell correlates and PD-1+ lymphocytes in sentinel lymph node melanoma metastases

Tumor PD-L1 expression, immune cell correlates and PD-1+ lymphocytes in sentinel lymph node melanoma metastases

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

781 Melanoma subtypes demonstrate distinct PD-L1 expression profiles

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