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Clin Cancer Res. 2019 Apr 15;25(8):2442-2449. doi: 10.1158/1078-0432.CCR-18-2652. Epub 2019 Jan 7.

Multiplex Quantitative Analysis of Tumor-Infiltrating Lymphocytes and Immunotherapy Outcome in Metastatic Melanoma.

Author information

1
Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
2
Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
3
Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut.
4
Department of Dermatology, Yale School of Medicine, New Haven, Connecticut.
5
Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
6
Department of Pathology, Yale School of Medicine, New Haven, Connecticut. david.rimm@yale.edu.

Abstract

PURPOSE:

Because durable response to programmed cell death 1 (PD-1) inhibition is limited to a subset of melanoma patients, new predictive biomarkers could have clinical utility. We hypothesize that pretreatment tumor-infiltrating lymphocyte (TIL) profiles could be associated with response.

EXPERIMENTAL DESIGN:

Pretreatment whole tissue sections from 94 melanoma patients treated with anti-PD-1 therapy were profiled by multiplex immunofluorescence to perform TIL quantification (CD4, CD8, CD20) and assess TIL activation (CD3, GZMB, Ki67). Two independent image analysis technologies were used: inForm (PerkinElmer) to determine cell counts, and AQUA to measure protein by quantitative immunofluorescence (QIF). TIL parameters by both methodologies were correlated with objective response or disease control rate (ORR/DCR) by RECIST 1.1 and survival outcome.

RESULTS:

Pretreatment lymphocytic infiltration, by cell counts or QIF, was significantly higher in complete or partial response than in stable or progressive disease, particularly for CD8 (P < 0.0001). Neither TIL activation nor dormancy was associated with outcome. CD8 associations with progression-free survival (HR > 3) were independently significant in multivariable analyses and accounted for similar CD3 associations in anti-PD-1-treated patients. CD8 was not associated with melanoma prognosis in the absence of immunotherapy. Predictive performance of CD8 cell count (and QIF) had an area under the ROC curve above 0.75 (ORR/DCR), which reached 0.83 for ipilimumab plus nivolumab.

CONCLUSIONS:

Pretreatment lymphocytic infiltration is associated with anti-PD-1 response in metastatic melanoma. Quantitative TIL analysis has potential for application in digital precision immuno-oncology as an "indicative" companion diagnostic.

PMID:
30617133
PMCID:
PMC6467753
[Available on 2020-04-15]
DOI:
10.1158/1078-0432.CCR-18-2652

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