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Figure 1.
Copy Number Gain of CD274 and PDCD1LG2 in a Case of Cervical Squamous Cell Carcinoma
Copy Number Gain of CD274 and PDCD1LG2 in a Case of Cervical Squamous Cell Carcinoma

Copy number variation of targeted genetic loci on chromosome 9 as detected by a clinically deployed targeted sequencing assay (OncoPanel; Brigham and Women’s Hospital). Each dot represents 1 targeted DNA segment (generally corresponding to 1 exon) arranged sequentially along the chromosome 9 from the p to q arm. C indicates centromere. The vertical axis is the ratio of the number of sequence reads for the specimen vs a panel of normals in log base 2 scale. A value of 0 denotes no difference from normal (diploid), and a log2 ratio greater than 1.5 indicates more than a 3-copy gain. Relative numbers of reads within CD274 (cyan dots) and PDCD1LG2 (orange dots) are indicated. One additional gene (JAK2 [gray dots telomeric to CD274]) also showed copy gain by this assay, but additional genes on chromosome 9 did not.

Figure 2.
CD274 and PDCD1LG2 Status and PD-L1 Protein Expression in Cervical Squamous Cell Carcinoma With Copy Gain Identified by a Next-Generation Sequencing Assay
CD274 and PDCD1LG2 Status and PD-L1 Protein Expression in Cervical Squamous Cell Carcinoma With Copy Gain Identified by a Next-Generation Sequencing Assay

Formalin fixed paraffin embedded tissue from the cervical squamous cell carcinoma shown in Figure 1 (A) hybridized with probes targeting CD274 (red), PDCD1LG2 (green), and the centromeric region of chromosome 9 (aqua) and showing increased copies of CD274 and PDCD1LG2 relative to the centromeric region of chromosome 9, and (B) immunostained with anti-PD-L1 antibody and showing intense positive staining (brown coloration) of tumor cell membranes.

Figure 3.
Examples of CD274 and PDCD1LG2 FISH and PD-L1 IHC in Cervical Squamous Cell Carcinomas
Examples of CD274 and PDCD1LG2 FISH and PD-L1 IHC in Cervical Squamous Cell Carcinomas

Fluorescence in situ hybridization for CD274 (red) and PDCD1LG2 (green), and the centromeric region of chromosome 9 (aqua) and corresponding immunohistochemical staining for PD-L1 (positive staining = brown coloration) shown in the inset for cervical squamous cell carcinomas categorized as (A) coamplification, (B) cogain, (C) polysomy, and (D) disomy for CD274 and PDCD1LG2. FISH indicates fluoresence in situ hybridization; IHC, immunohistochemical.

Figure 4.
Levels of PD-L1 Expression by Genetic Category in Cervical Squamous Cell Carcinoma
Levels of PD-L1 Expression by Genetic Category in Cervical Squamous Cell Carcinoma

PD-L1 H scores by genetic category in cervical squamous cell carcinomas demonstrated by box and whisker plots showing median score (horizonal line), 25th to 75th percentiles (boxes), and minimum and maximum scores (whiskers). H scores are the product of the percentage of tumor cells with positive staining (0-100) and the maximum intensity of positive staining (1, 2, or 3).

Figure 5.
p16INK4A Expression and Levels of PD-L1 Expression by Genetic Category in Vulvar Squamous Cell Carcinomas
p16INK4A Expression and Levels of PD-L1 Expression by Genetic Category in Vulvar Squamous Cell Carcinomas

A, Total number of cases within each genetic category with numbers of p16− cases in darker shade. B, Box and whisker plots showing median (horizontal line), 25th to 75th percentiles (boxes), and minimum and maximum H scores (whiskers) for tumors analyzed within each genetic category (P = .002). H scores are the product of the percentage of tumor cells with positive staining (0-100) and the maximum intensity of positive staining (1, 2, or 3).

1.
Vesely  MD, Kershaw  MH, Schreiber  RD, Smyth  MJ.  Natural innate and adaptive immunity to cancer.  Annu Rev Immunol. 2011;29:235-271.PubMedGoogle ScholarCrossref
2.
Postow  MA, Callahan  MK, Wolchok  JD.  Immune Checkpoint Blockade in Cancer Therapy.  J Clin Oncol. 2015;33(17):1974-1982.PubMedGoogle ScholarCrossref
3.
Topalian  SL, Hodi  FS, Brahmer  JR,  et al.  Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.  N Engl J Med. 2012;366(26):2443-2454.PubMedGoogle ScholarCrossref
4.
Howitt  BE, Sholl  LM, Dal Cin  P,  et al.  Targeted genomic analysis of Müllerian adenosarcoma.  J Pathol. 2015;235(1):37-49.PubMedGoogle ScholarCrossref
5.
Cryan  JB, Haidar  S, Ramkissoon  LA,  et al.  Clinical multiplexed exome sequencing distinguishes adult oligodendroglial neoplasms from astrocytic and mixed lineage gliomas.  Oncotarget. 2014;5(18):8083-8092.PubMedGoogle ScholarCrossref
6.
Green  MR, Monti  S, Rodig  SJ,  et al.  Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma.  Blood. 2010;116(17):3268-3277.PubMedGoogle ScholarCrossref
7.
Ansell  SM, Lesokhin  AM, Borrello  I,  et al.  PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma.  N Engl J Med. 2015;372(4):311-319.PubMedGoogle ScholarCrossref
8.
Chen  BJ, Chapuy  B, Ouyang  J,  et al.  PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies.  Clin Cancer Res. 2013;19(13):3462-3473.PubMedGoogle ScholarCrossref
9.
Ho  C, Rodig  SJ.  Immunohistochemical markers in lymphoid malignancies: Protein correlates of molecular alterations.  Semin Diagn Pathol. 2015;32(5):381-391.PubMedGoogle ScholarCrossref
10.
Keating  JT, Ince  T, Crum  CP.  Surrogate biomarkers of HPV infection in cervical neoplasia screening and diagnosis.  Adv Anat Pathol. 2001;8(2):83-92.PubMedGoogle ScholarCrossref
11.
O’Neill  CJ, McCluggage  WG.  p16 expression in the female genital tract and its value in diagnosis.  Adv Anat Pathol. 2006;13(1):8-15.PubMedGoogle ScholarCrossref
12.
Grønhøj Larsen  C, Gyldenløve  M, Jensen  DH,  et al.  Correlation between human papillomavirus and p16 overexpression in oropharyngeal tumours: a systematic review.  Br J Cancer. 2014;110(6):1587-1594.PubMedGoogle ScholarCrossref
13.
Green  MR, Rodig  S, Juszczynski  P,  et al.  Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy.  Clin Cancer Res. 2012;18(6):1611-1618.PubMedGoogle ScholarCrossref
14.
Ouyang  J, Juszczynski  P, Rodig  SJ,  et al.  Viral induction and targeted inhibition of galectin-1 in EBV+ posttransplant lymphoproliferative disorders.  Blood. 2011;117(16):4315-4322.PubMedGoogle ScholarCrossref
15.
Karim  R, Jordanova  ES, Piersma  SJ,  et al.  Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell infiltration and survival of patients with cervical carcinoma.  Clin Cancer Res. 2009;15(20):6341-6347.PubMedGoogle ScholarCrossref
Brief Report
April 2016

Genetic Basis for PD-L1 Expression in Squamous Cell Carcinomas of the Cervix and Vulva

Author Affiliations
  • 1Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts
  • 2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston Massachusetts
  • 3Departments of Obstetrics and Gynecology, Radiation Oncology, and Gynecological Oncology, Brigham and Women’s Hospital, Boston, Massachusetts
  • 4The Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 5Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
 

Copyright 2016 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.

JAMA Oncol. 2016;2(4):518-522. doi:10.1001/jamaoncol.2015.6326
Abstract

Importance  Patients with squamous cell carcinoma (SCC) of the cervix or vulva have limited therapeutic options, and the potential for immunotherapy for this population has not been evaluated. Recent trials suggest that tumors with a genetic basis for PD-1 (programmed cell death protein 1) ligand expression are highly sensitive to therapeutic antibodies targeting PD-1.

Objective  To determine the genetic status of CD274 (encoding PD-L1 [programmed cell death 1 ligand 1]) and PDCD1LG2 (encoding PD-L2 [programmed cell death 1 ligand 2]) in SCCs of the cervix and vulva and to correlate the findings with PD-L1 protein expression.

Design, Setting, and Participants  We performed fluorescence in situ hybridization (FISH) using probes targeting CD274, PDCD1LG2, and the centromeric portion of chromosome 9, and immunohistochemistry (IHC) using an antibody recognizing PD-L1 on formalin-fixed, paraffin-embedded (FFPE) biopsy specimens from 48 cervical SCCs and 23 vulvar SCCs.

Main Outcomes and Measures  Tumors were categorized according to the genetic abnormality in CD274 and PDCD1LG2 (coamplification > cogain > polysomy > disomy) as detected by FISH, and evaluated on a semiquantitative scale (modified H score, the product of the percentage of tumor cells with positive staining and the maximum intensity of positive staining) for PD-L1 protein expression as detected by IHC.

Results  Overall, 71 samples of FFPE tissue from cases of cervical SCCs (n = 48) and vulvar SCCs (n = 23) were retrieved from the archives of Brigham and Women’s Hospital and included in this study. We observed cogain or coamplification of CD274 and PDCD1LG2 in 32 of 48 cervical SCCs (67%) and 10 of 23 vulvar SCCs (43%). Median PD-L1 protein expression was highest among tumors with CD274 and PDCD1LG2 coamplification and lowest among tumors with disomy.

Conclusions and Relevance  Recurrent copy number gain of the genes encoding the PD-1 ligands provides a genetic basis for PD-L1 expression in a subset of cervical and vulvar SCCs and identifies a class of patients that are rational candidates for therapies targeting PD-1.

Introduction

Tumors employ strategies of immune evasion to survive and spread.1 A major mechanism involves expression of programmed cell death 1 ligands 1 and 2 (PD-L1, PD-L2) by tumor cells that bind PD-1 (programmed cell death protein 1) on effector T cells to suppress antitumor cellular immunity.2 Clinical responses to PD-1 blockade are associated with PD-L1 expression by malignant tumor cells and provide a rationale for screening individual tumors to identify patients most likely to benefit.3 However, the biological basis for the expression of the PD-1 ligands in solid tumors is poorly understood. We examined the integrity of the CD274 (encoding PD-L1) and PDCD1LG2 (encoding PD-L2) loci in a series of squamous cell carcinomas (SCC) of the cervix and vulva and correlated our findings with PD-L1 protein expression in the tumor.

Methods
Case Selection

Samples of formalin-fixed, paraffin-embedded (FFPE) tissue from cases of cervical SCCs (n=48) and vulvar SCCs (n=23) were retrieved from the archives of Brigham and Women’s Hospital and included in this study. Additionally, data collected on cervical SCCs analyzed with a clinically deployed next-generation sequencing (NGS) assay were reviewed for evidence of selective copy gain of CD274 and PDCD1LG2 at 9p24 (eMethods in the Supplement).4-6 Copy number analysis of CD274 in cervical SCCs from The Cancer Genome Atlas (TCGA) (http://www.cbioportal.org; accessed 5/1/2015) (eTable 1 in the Supplement) was also obtained. Brigham and Women’s Hospital provided institutional review board approval.

Fluorescence In Situ Hybridization

We performed fluorescence in situ hybridization (FISH) on FFPE sections of tumors with probes targeting CD274, PDCD1LG2, and the centromeric region of chromosome 9.7 Nuclei with a target:control ratio of greater or equal to 3:1 were scored as amplified; less than 3:1 but greater than 1:1 were scored as relative gain; and 1:1 as either polysomy (>2 copies), disomy (2 copies), or monosomy (<2 copies) (eMethods in the Supplement).7 Cases were categorized according to the maximum genetic abnormality observed by FISH analysis (amplification > gain > polysomy > disomy).7

Immunohistochemistry

Immunohistochemistry was performed on all cases with a monoclonal antibody recognizing PD-L17-9 (eMethods in the Supplement). PD-L1 stained slides were scored by both maximal intensity of staining (0, negative; 1, weak; 2, moderate; 3, strong) and percentage of tumors cells positive (0%-100%; with any intensity of positive staining) to generate a modified H score (range, 0-300).

Statistics

Data were summarized descriptively. The exact Kruskal-Wallis test was applied across the ordered categories of dysregulation (disomy, polysomy, cogain, and coamplification) to assess changes in H score related to degree of dysregulation. Graphs were generated with GraphPad Prism 5 software (GraphPad Software, Inc), and P values less than .05 were considered statistically significant; there was no adjustment for multiplicity of testing.

Results
Cervical Squamous Cell Carcinoma

The NGS assay revealed 3 of 24 (12.5%) cervical SCCs with copy gains of CD274 and PDCD1LG2 at chromosome 9p24.1 (Figure 1 and data not shown). One case had tissue available for additional analyses, and we performed FISH using probes targeting CD274 and PDCD1LG2.7 We observed high level coamplification of CD274 and PDCD1LG2 in 96% of the tumor cells, with up to 15 copies of both genes per cell (Figure 2A). Cogain of CD274 and PDCD1LG2 was present in the remaining 4% of tumor cells analyzed. Immunohistochemical staining with an antibody specific for PD-L1 revealed robust protein expression (2+ intensity) in 95% of the tumor cells (modified H score, 190)8 with predominantly membranous staining pattern (Figure 2B).

We then evaluated an additional cohort of 47 cervical SCCs lacking previous genomic annotation (for a total of 48 cervical SCCs) with the FISH assay. We observed coamplification or cogain of CD274 and PDCD1LG2 in 32 of 48 (67%) cases (Figures 3 and 4). Overall, 9 of 48 (19%) cases were categorized as polysomic and 7 of 48 (15%) disomic for chromosome 9. There was copy number heterogeneity within each category. Cases with tumor cells showing coamplification of CD274 and PDCD1LG2, and categorized as such, also included malignant cells with lesser degrees of gain for CD274 and PDCD1LG2 (cogain, polysomy, and disomy). Similarly, tumors categorized as cogain included malignant cells with polysomy and disomy. Occasional cases included malignant cells with relative loss of CD274 and PDCD1LG2 or monosomy 9 (eTable 2 in the Supplement). In no case did we observe discordant alterations of CD274 and PDCD1LG2.

Independent scoring of immunohistochemistry for all cases revealed a range of PD-L1 protein expression across tumors with highest median expression in cases with coamplification of CD274 and PDCD1LG2 and lowest in cases with disomy (Figures 3 and 4) (eFigure 1 in the Supplement). PD-L1 expression, when observed, was accentuated at the cell membrane of the tumor cells (Figure 3).

For independent validation of the genetic alterations we observed in our cohort of cases, we interrogated TCGA data for cervical SCCs and found evidence for amplification or gain of CD274 in 28 of 129 (22%) cases (eTable 1 in Supplement).

Vulvar Squamous Cell Carcinoma

While cervical SCCs are associated with high-risk human papilloma virus (HPV) in the great majority of cases,10 vulvar SCCs have both HPV-related and HPV-unrelated mechanisms of pathogenesis. We examined a series of 23 vulvar SCCs using p16(INK4a) as a sensitive and specific surrogate biomarker of high-risk HPV infection.11,12 Overall, 6 cases (26%) showed coamplification of CD274 and PDCD1GL2, 4 cases (17%) showed cogain, 6 cases (26%) showed polysomy, and 7 cases (30%) showed disomy (Figure 5A). Vulvar SCCs positive for p16 (n = 7 [30%]) included 2 cases with cogain of CD274 and PDCD1LG2, 1 with polysomy, and 4 with disomy (Figure 5A). Vulvar SCCs negative for p16 (n = 16 [70%]) included 6 cases with coamplification, 2 with cogain, 5 with polysomy, and 3 with disomy. There was no association between p16 status and the genetic category of the tumor (P = .08). Immunohistochemical staining for PD-L1 across all cases revealed the highest median PD-L1 protein expression among cases with coamplification of CD274 and PDCD1LG2 and decreasing values with decreasing genetic complexity (Figure 5B) (eFigure 2 in the Supplement).

Discussion

Our data reveal that selective copy number gain of CD274 and PDCD1LG2 at 9p24.1 occurs frequently in SCCs of the cervix and vulva and provides a genetic basis for increased PD-L1 protein expression in these tumor types. To date, the most detailed analysis of 9p24.1 alterations has been in classical Hodgkin lymphoma (cHL), in which malignant Reed-Sternberg cells have 9p24.1/CD274/PDCD1LG2 copy gain and increased expression of the PD-1 ligands.6 We have also reported that Epstein-Barr virus–encoded signaling proteins contribute to PD-1 ligand expression in primary cells.13,14 It remains to be established whether HPV-encoded proteins have a similar role in SCCs.15 However, the data presented here suggest that 9p24.1 gene copy number alterations are a major mechanism of increased PD-L1 expression in SCCs of the cervix and vulva, irrespective of viral infection.

A recent trial7 of single agent nivolumab in patients with relapsed and/or refractory cHL revealed the highest overall response rate (87%) reported to date for an individual tumor type. Tissue biopsies were available for a subset of patients in this trial, and all showed copy gain of CD274 and PDCD1LG2. These results suggest that tumors with a genetic basis for PD-1 ligand expression may be uniquely sensitive to PD-1 blockade.7

Conclusions

We show that cogain or coamplification of CD274 and PDCD1LG2 is common in cervical and vulvar SCCs, and provides a genetic basis for PD-L1 expression. Thus, a significant proportion of patients with these tumors are rational candidates for clinical trials of PD-1 blockade.

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Article Information

Corresponding Author: Scott J. Rodig, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115 (srodig@partners.org).

Accepted for Publication: December 15, 2015.

Published Online: February 25, 2016. doi:10.1001/jamaoncol.2015.6326.

Author Contributions: Drs Howitt and Rodig had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Howitt, Aviki, Pak, Connelly, Gjini, Ligon, Freeman, Hodi, Shipp, Rodig.

Acquisition, analysis, or interpretation of data: Howitt, Sun, Roemer, Kelley, Chapuy, Aviki, Pak, Gjini, Shi, Lee, Viswanathan, Horowitz, Neuberg, Crum, Lindeman, Kuo, Ligon, Hodi, Shipp, Rodig.

Drafting of the manuscript: Howitt, Sun, Gjini, Crum, Rodig.

Critical revision of the manuscript for important intellectual content: Howitt, Roemer, Kelley, Chapuy, Aviki, Pak, Connelly, Gjini, Shi, Lee, Viswanathan, Horowitz, Neuberg, Crum, Lindeman, Kuo, Ligon, Freeman, Hodi, Shipp, Rodig.

Statistical analysis: Howitt, Kelley, Aviki, Gjini, Neuberg, Kuo, Rodig.

Obtained funding: Shipp, Rodig.

Administrative, technical, or material support: Howitt, Sun, Roemer, Aviki, Pak, Connelly, Lee, Viswanathan, Crum, Lindeman, Kuo, Freeman, Hodi, Rodig.

Study supervision: Howitt, Chapuy, Gjini, Lindeman, Ligon, Shipp, Rodig.

Cohort Selection and Bioinformatics Analysis: Shi.

Conflict of Interest Disclosures: Dr Freeman has patents associated with the detection of the PD-1 ligands for diagnostic purposes, and Drs Hodi, Shipp, and Rodig receive research support through the International Immune Oncology Network (I-ION) of Bristol-Meyers Squibb. No other conflicts are reported.

Funding/Support: Funding and support was provided by the Center for Immuno-Oncology (CIO) at the Dana-Farber Cancer Institute, a grant from the International Immuno-Oncology Network (IION) sponsored by Bristol-Myers-Squibb, and the National Institutes of Health (grant No. R01 NIH/NCI CA161026 [M.A.S.]).

Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Vesely  MD, Kershaw  MH, Schreiber  RD, Smyth  MJ.  Natural innate and adaptive immunity to cancer.  Annu Rev Immunol. 2011;29:235-271.PubMedGoogle ScholarCrossref
2.
Postow  MA, Callahan  MK, Wolchok  JD.  Immune Checkpoint Blockade in Cancer Therapy.  J Clin Oncol. 2015;33(17):1974-1982.PubMedGoogle ScholarCrossref
3.
Topalian  SL, Hodi  FS, Brahmer  JR,  et al.  Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.  N Engl J Med. 2012;366(26):2443-2454.PubMedGoogle ScholarCrossref
4.
Howitt  BE, Sholl  LM, Dal Cin  P,  et al.  Targeted genomic analysis of Müllerian adenosarcoma.  J Pathol. 2015;235(1):37-49.PubMedGoogle ScholarCrossref
5.
Cryan  JB, Haidar  S, Ramkissoon  LA,  et al.  Clinical multiplexed exome sequencing distinguishes adult oligodendroglial neoplasms from astrocytic and mixed lineage gliomas.  Oncotarget. 2014;5(18):8083-8092.PubMedGoogle ScholarCrossref
6.
Green  MR, Monti  S, Rodig  SJ,  et al.  Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma.  Blood. 2010;116(17):3268-3277.PubMedGoogle ScholarCrossref
7.
Ansell  SM, Lesokhin  AM, Borrello  I,  et al.  PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma.  N Engl J Med. 2015;372(4):311-319.PubMedGoogle ScholarCrossref
8.
Chen  BJ, Chapuy  B, Ouyang  J,  et al.  PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies.  Clin Cancer Res. 2013;19(13):3462-3473.PubMedGoogle ScholarCrossref
9.
Ho  C, Rodig  SJ.  Immunohistochemical markers in lymphoid malignancies: Protein correlates of molecular alterations.  Semin Diagn Pathol. 2015;32(5):381-391.PubMedGoogle ScholarCrossref
10.
Keating  JT, Ince  T, Crum  CP.  Surrogate biomarkers of HPV infection in cervical neoplasia screening and diagnosis.  Adv Anat Pathol. 2001;8(2):83-92.PubMedGoogle ScholarCrossref
11.
O’Neill  CJ, McCluggage  WG.  p16 expression in the female genital tract and its value in diagnosis.  Adv Anat Pathol. 2006;13(1):8-15.PubMedGoogle ScholarCrossref
12.
Grønhøj Larsen  C, Gyldenløve  M, Jensen  DH,  et al.  Correlation between human papillomavirus and p16 overexpression in oropharyngeal tumours: a systematic review.  Br J Cancer. 2014;110(6):1587-1594.PubMedGoogle ScholarCrossref
13.
Green  MR, Rodig  S, Juszczynski  P,  et al.  Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy.  Clin Cancer Res. 2012;18(6):1611-1618.PubMedGoogle ScholarCrossref
14.
Ouyang  J, Juszczynski  P, Rodig  SJ,  et al.  Viral induction and targeted inhibition of galectin-1 in EBV+ posttransplant lymphoproliferative disorders.  Blood. 2011;117(16):4315-4322.PubMedGoogle ScholarCrossref
15.
Karim  R, Jordanova  ES, Piersma  SJ,  et al.  Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell infiltration and survival of patients with cervical carcinoma.  Clin Cancer Res. 2009;15(20):6341-6347.PubMedGoogle ScholarCrossref
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