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Multicenter Study
. 2014 Oct 1;20(19):5064-74.
doi: 10.1158/1078-0432.CCR-13-3271. Epub 2014 Apr 8.

"V体育安卓版" Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy

Janis M Taube  1 , Alison Klein  2 , Julie R Brahmer  3 , Haiying Xu  4 , Xiaoyu Pan  3 , Jung H Kim  4 , Lieping Chen  5 , Drew M Pardoll  3 , Suzanne L Topalian  6 , Robert A Anders  7
Affiliations
Multicenter Study

"VSports" Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy

Janis M Taube et al. Clin Cancer Res. .

Abstract

Purpose: Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies VSports手机版. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization. .

Experimental design: Patients (N = 41) with melanoma, non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate cancer were treated on an early-phase trial of anti-PD-1 (nivolumab) at one institution and had evaluable pretreatment tumor specimens. Immunoarchitectural features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell infiltration, and lymphocyte subpopulations, were assessed for interrelationships and potential correlations with clinical outcomes V体育安卓版. .

Results: Membranous (cell surface) PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In the overall cohort, PD-L1 expression was geographically associated with infiltrating immune cells (P < 0. 001), although lymphocyte-rich regions were not always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and immune infiltrates was significantly associated with expression of PD-1 on lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1 expression V体育ios版. Tumor cell PD-L1 expression correlated with objective response to anti-PD-1 therapy, when analyzing either the specimen obtained closest to therapy or the highest scoring sample among multiple biopsies from individual patients. These correlations were stronger than borderline associations of PD-1 expression or the presence of intratumoral immune cell infiltrates with response. .

Conclusions: Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti-PD-1 blockade. Clin Cancer Res; 20(19); 5064-74. ©2014 AACR VSports最新版本. .

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Figures

Figure 1
Figure 1. Association of tumor PD-L1 expression with immune infiltrates
Left column: IHC for PD-L1. Right column: IHC for CD3+ TILs. Panel (A), representative specimen from a subcutaneous melanoma metastasis demonstrating focal PD-L1 expression by tumor cells geographically associated with TILs. Panel (B), diffuse membranous tumor cell PD-L1 expression in a NSCLC brain metastasis, not associated with TILs. Panels (C), colorectal carcinoma metastasis to liver with membranous PD-L1 expression on infiltrating immune cells (brown stain) but not on tumor cells (asterisks). Original magnification 200×, all panels. Higher power images and additional immunohistochemical studies of the representative melanoma and colorectal carcinoma case are shown in Supplementary Figures 2 and 3.
Figure 2
Figure 2. Immunoarchitechture within a melanoma lymph nodal metastasis
On a section stained with H&E (upper left), a tumor deposit is indicated by arrows and lymph node germinal centers by asterisks. Expression of PD-1, PD-L1 and PD-L2 was observed in the lymph node germinal centers, providing an internal positive control for staining. Within the tumor deposit, PD-L1 and PD-L2 were expressed by both tumor and infiltrating immune cells, associated geographically with PD-1 expression. Additional characterization of the immune infiltrate is provided in Supplementary Figure 4. Original magnification 100×, all panels.
Figure 3
Figure 3. Association of PD-L2 expression in the tumor microenvironment with PD-L1 expression by tumor cells
PD-L2 expression as assessed by IHC was positive in 8 of 38 tumor specimens, and was expressed on tumor cells and/or immune infiltrating cells. Although PD-L2 was observed less frequently than PD-L1 expression, when present, it was almost always geographically associated with tumor cell PD-L1 expression.
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References (V体育ios版)

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