Table 1.

PD-1, B7-H1, and B7-DC expression and prognostic significance in cancer patients

DiseaseCitationnDetection method/Ab clonesLocation of PD-L ExpressionNotes on T-cell InfiltratePathologic ObservationsPrognosis
Malignant brain tumors(80)83FACS; anti-PD-1, B7-H1, and B7-DC (BD Pharmingen)N/AVariable; 6 of 23 tumors with TIL had PD-1+ CD4+ lymphocytes, with PD-1 expression significantly higher than on the intratumoral Tregs of these patients (P = 0.005)61% of brain tumors (but no WHO grade 1 tumors) expressed PD-L1 and none expressed PD-L2N/A
Cervical cancer(44)115Paraffin IHC; anti-B7-H1 (5H1), B7-DC and PD-1 (R&D)PD-L1/2 on tumor cell membrane and throughout tumor bedPD-L1 expression was associated with higher intraepithelial infiltration by Foxp3+ T cells (P = 0.022) but not with CD8+ T cells, and more intraepithelial PD-1+ T cells (not significant)19% of tumor samples expressed PD-L1 and 29% expressed PD-L2; in patients with PD-L1+ or PD-L1 tumors, more than half of the infiltrating CD8+ T cells and half of the Foxp3+ T cells expressed PD-1; PD-L2 expression did not correlate with prognosis but did correlate with adenocarcinoma subtype (P = 0.012) and more advanced disease (P = 0.013)No direct effect of PD-L1 expression on prognosis; OS of patients with PD-L1+ tumors and a low CD8+/FoxP3+ T-cell ratio was better than in patients with a PD-L1 tumor and a low CD8+/FoxP3+ T-cell ratio (P = 0.033)
Pancreatic cancer(50)51Frozen IHC; anti-B7-H1 (MIH1); anti-B7-DC (MIH18)B7-H1 and B7-DC were expressed in plasma membrane and cytoplasm of cancer cells; also found in some TILs and stromal cellsPD-L1 expression was inversely correlated with TILs (CD4+ T cells, P = 0.019; CD8+ T cells, P < 0.0001)20 of 51 tumor samples were B7-H1+ and 14 of 51 tumor samples were B7-DC+; no correlation between tumor B7-H1 status and tumor/nodal/metastatic status or pathologic stageB7-H1+ patients had poorer prognosis than the B7-H1 negative patients (P = 0.016); no correlation of tumor B7-DC expression with patient survival; B7-H1 was an independent prognostic factor (P = 0.022)
Urothelial cancer(81)65Frozen IHC; anti-B7-H1 (MIH1)B7-H1 present on plasma membrane and/or cytoplasm of urothelial cancer cells in a focal patternIn 13 cases selected for examination, most TILs expressed high levels of PD-1B7-H1 expression correlated with WHO grade (P < 0.001) and primary tumor classification (P = 0.031); no association between B7-H1 expression and primary node or stage classificationIncreased B7-H1 expression was associated with poor survival (P = 0.021) and increased likelihood of postresection recurrence (P = 0.026)
Gastric cancer(82)102Paraffin IHC; anti-B7-H1 (2H11)B7-H1 was expressed predominantly in the cytoplasm; some nuclear membrane localization was also presentN/A42.2% of gastric carcinoma tissues were B7-H1+; B7-H1 correlated with tumor size, invasion, and lymph node metastasis (P < 0.01, 0.05, 0.01, respectively)B7-H1 expression was an independent prognostic factor (P = 0.040) and correlated with reduced patient survival (P < 0.01)
Esophageal cancer(49)41Frozen IHC, mRNA analysis; anti-B7-H1 (MIH1), anti-B7-DC (MIH18)cCytoplasmic or membranousPD-L2 mRNA expression inversely correlated with presence of tumor-infiltrating CD8+ T cells (P = 0.011)N/APD-L1 and PD-L2 mRNA expression were associated with decreased OS (P = 0.025 and P = 0.003, respectively) and were independent predictors of worse prognosis
RCC(48)306Paraffin IHC; anti-B7-H1 (5H1)Tumors were considered B7-H1+ if ≥5% of tumor cells had cell-surface stainingN/AB7-H1+ tumors were associated with 2002 TNM stage III or IV, tumor size of ≥5 cm, nuclear grade 3 or 4, and coagulative tumor necrosis (all P < 0.001)Patients with B7-H1+ tumors had increased risk of death from RCC [risk ratio (RR), 3.92; P < 0.001] and overall mortality (RR, 2.37; P < 0.001), and decreased 5-year survival (41.9% for patients with B7-H1+ tumors vs. 82.9% for patients with B7-H1 tumors)
NSCLC(83)109Paraffin IHC; anti-B7-H1 (clone not specified)PD-L1 on membrane and in cytoplasm of tumor cells, in cluster and scattered patterns within tumorsCD1a+ TIDC were increased in PD-L1+ sections of tumora and had higher expression of PD-L1 than CD83+ DCPD-L1+ cells in adenocarcinoma were more numerous than those in squamous cell carcinoma (65.2% vs 44.4%, P = 0.032)PD-L1 positivity correlated with survival shorter than 3 years after lobectomy (P = 0.034)
(45)52Frozen IHC; anti-B7-H1 (MIH1), anti-B7-DC (MIH14)Cytoplasmic, membranous, or cytoplasmic and membranous B7-H1 and B7-DC staining was observed in focal or scattered patterns in all 52 specimens of NSCLCThere were fewer TILS overall and fewer PD-1+ TILs in B7-H1+ regions of tumor than in B7-H1 regions of tumor (P = 0.01, 0.02) in a subset of 5 patientsNo correlation of B7-H1 or B7-DC expression with clinicopathologic characteristicsNo correlation between B7-H1 or B7-DC expression and patient survival
Glioma(84)10Frozen IHC; anti-B7-H1 (5H1)B7-H1 expression was detected in all 10 glioma samples examined; B7-H1+ cells were scattered evenly throughout the specimensbN/AN/AN/A
Hepatocellular carcinoma(51)240 and 125Paraffin IHC; anti-B7-H1 (eBioscience) and B7-DC (R&D)Both ligands present on membrane and/or cytoplasm of tumor cells, in scattered (most cases) or focal patternsPositive correlation between B7-H1 expression and FoxP3+ Treg infiltration (P = 0.009) as well as between B7-DC expression and Treg infiltration (P = 0.002)B7-H1+ patients harbored more tumors with vascular invasion, whereas B7-DC+ patients had more tumor vascular invasion and advanced TNM stagePatients with PD-L1+ tumors had poorer DFS and OS than patients with PD-L1 tumors; tumor PD-L1 status was an independent prognostic factor for DFS, and PD-L1+ patients were nearly 2 times more likely to suffer from relapse after resection than PD-L1 patients
(85)26Frozen IHC; anti-PD-1 (J116), B7-H1 (MIH1), and B7-DC (MIH18, eBiosciences)Focal or scatteredPD-1+ T cells accumulated within tumors and in peritumoral areasPD-L expression was restricted mainly to Kupffer cells and liver sinusoidal endothelial cells; 24 of 26 HCC specimens expressed PD-L1, whereas 23 of 26 expressed PD-L2; PD-L1 expression was associated with earlier tumor stage (P = 0.018)N/A
(86)56Paraffin IHC, FACS; anti-PD-1 (R&D), B7-H1 (Biolegend); FACS with PE-conjugated PD-1 and B7-H1 (eBiosciences)Seems to be both cytoplasmic and membranousbPD-1 expression was increased on TILs in comparison with PBMC and noninfiltrating lymphocytes (P < 0.001, 0.001, respectively)CD8+ T cells were mainly distributed around the PD-L1+ portion of tumor nestPatients with high levels of intratumoral PD-1+ CD8+ T cells had shorter DFS than those with low levels (P < 0.001)
Melanoma(87)59Paraffin IHC; anti-B7-H1 (clone 27A2, MBL)N/AIn 2 patients, PD-1 expression on CD8+ cells increased as disease progressedBTT in the PD-L1hi expression group was higher than in the PD-L1lo expression group (P = 0.0298); T3–T4 tumors had higher PD-L1 expression than T0–T2 tumors (P = 0.0072); PD-L1 expression in primary tumors from patients with LN metastasis was higher than that in patients without LN metastasis (P = 0.0375); PD-L1 expression in metastatic LNs was higher than in nonmetastatic LNs (P < 0.0001)OS and PFS rate were lower in the PD-L1hi expression group compared with the PD-L1lo expression group (P = 0. 0402, 0.0522 respectively), indicating that PD-L1 expression is an independent predictor of OS and DFS
(47)150Paraffin IHC; anti-B7-H1 mAb (5H1) or anti-B7-H1 polyclonal Ab (4059, ProSci)Membranous PD-L1 expression by melanocytes within the tumors had 3 patterns: no PD-L1; regional expression of PD-L1 on melanocytes colocalized with TILs (most common); and PD-L1 expression in the absence of TILsAlmost all PD-L1+ tumors were associated with TILs, whereas only 28% of PD-L1 tumors were associated with TILs; a sample of PD-L1+ tumors with TIL were shown to contain IFN-γ, whereas no PD-L1 tumors examined contained IFN-γPD-L1 was expressed on a proportion (57 of 150) of various MEL lesions, most commonly in close juxtaposition to TILs; when an inflammatory response to the tumor was detected, it was likely that both the tumor and infiltrating cells were PD-L1+; PD-L1 expression was associated with the superficial spreading and nodular MEL subtypes (P = 0.033) and not with MEL stagePatients with PD-L1+ mMEL had longer survival than those with PD-L1 mMEL (P = 0.032); patients with mMEL with TILs had significantly improved survival compared with those without TILs (P = 0.017)
(88)35Paraffin IHC, FACS; anti-B7-H1 3.1 (D Olive); FACS with B7-H1, B7-DC, PD-1 mAbs (BD Pharmingen)B7-DC was present predominantly on myeloid cells, whereas B7-H1 was present on the surface of tumor cells, myeloid cells, or bothPD-1 expression was upregulated on T-cell populations extracted from primary tumors and metastases66% of mMEL biopsies were PD-L2+, whereas 58% of mMEL biopsies were PD-L1+N/A
Head and neck squamous cell carcinoma (HNSCC)(89)24Frozen IHC; anti-B7-H1 (5H1)11 of 24 specimens had intracytoplasmic staining, 11 of 24 tumors had membrane reactivity; 10 of 24 had bothN/A16 of 24 specimens (66%) had PD-L1 stainingN/A
(90)N/AAnti-B7-H1Majority of CD8+ TILs in HPV-HNSCC express PD-1Association between expression of PD-L1 on tumor cells and tumor-associated macrophages with the presence of TILs; tumor-cell PD-L1 and CD68+ APCs were found at the periphery of tumor beds in opposition to fronts of TILsN/A
Leukemia(91)30FACS, functional assays, frozen IHC; anti-B7-H1 (5H1)17/30 samples of human leukemia cells were B7-H1+N/AN/AN/A
Various(57)42Paraffin IHC; anti-B7-H1 (5H1)25 of 42 patients had tumor-cell surface PD-L1 stainingN/AN/AOf the 25 patients with PD-L1+ tumors, 9 experienced an objective response after treatment with anti-PD-1 antibody
(9)85Frozen IHC; anti-B7-H1 (5H1)B7-H1 present on majority of melanoma and carcinoma tissue and a few pulmonary macrophages in LC samples; B7-H1 observed in the plasma membrane, cytoplasm or both; in most cases, B7-H1 was expressed in a focal patternN/AN/AN/A
(13)130FACS, functional assays, frozen and paraffin IHC; anti-B7-H1 (29E.2A3, 29E.5A9 for FACS, functional assays and frozen IHC; 29E.2A3 for paraffin IHC)B7-H1 present on high percentage of thymic neoplasms, multiple carcinomas, and primary T-cell lymphomas but not B-cell non-Hodgkin lymphomabN/AN/AN/A
Ovarian cancer(52)70Paraffin IHC; anti-PD-1 (NAT, Abcam), anti-B7-H1 (27A2, MBL), anti-B7-DC (polyclonal, R&D)N/AN/ATIL PD-1 expression correlated with CD8+ (P = 0.002), CD4+ (P = 0.011), and CD57+ cell infiltration (P = 0.002) in the tumor; negative correlation between CD8+ cell infiltration and PD-L1 tumor expression; PD-L2 tumor expression was associated with FoxP3+ cell infiltrationHigh PD-L1 expression was an independent negative prognostic factor; patients with tumors with high immune cell infiltration (characterized by high PD-1, high CD4+ and CD8+ expression, among others) had better 5-year survival than patients with tumors without high TIL infiltration (84.6% vs. 55.2%, P = 0.041)
(12)N/AFACS, functional assays; anti-B7-H1 (BD Pharmingen for FACS, 5H1 for functional assays)B7-H1 present on nearly all myeloid dendritic cells from tumor ascites and from tumor-draining lymph nodesN/AN/AN/A
Prostate cancer(92)7FACS; anti-PD-1 (A. Korman, Medarex, Inc.)N/ACD8+ T-cell PD-1 was upregulated on cells infiltrating the prostate gland of patients with cancer (compared with those in peripheral blood, P < 0.0001); in some, almost 90% of prostate-infiltrating CD8+ T cells were PD-1+N/AN/A
Multiple myeloma(67)82FACS, Western blot analysis, mRNA analysis; anti-B7-H1 (M1H1 for FACS, N20 for Western blot analysis)B7-H1 present in most multiple myeloma plasma cell samples examinedN/AN/AN/A
Breast cancer(93)44FACS, frozen IHC; anti-B7-H1 (MIH1, eBiosciences)B7-H1 present in 22/44 breast cancer tissues examined (15/44 in tumor cells, 18/44 in TIL); staining was both membranous and cytoplasmicN/AIntratumoral B7-H1 expression was associated with histologic grade III–negative (P = 0.012), estrogen receptor–negative (P = 0.036), and progesterone receptor–negative (P = 0.040) patients; TIL B7-H1 was associated with large tumor size (P = 0.042), histologic grade 3 (P = 0.015), positivity of Her2/neu status (P = 0.019), and increased tumor lymphocyte infiltration (P = 0.001)N/A
Bladder cancer(94)280Frozen IHC; anti-B7-H1 (5H1)B7-H1 present in 28% of specimens examined; sample considered positive if ≥1% of tumor cells had membrane stainingB7-H1 expression associated with presence of TIL (P = 0.004)B7-H1 expression associated with high-grade tumors (P = 0.009)N/A

NOTE: Table does not include discussion of PD-1 on circulating T cells in these patients.

Abbreviations: BTT, Breslow tumor thickness; DFS, disease-free survival; FACS, fluorescence-activated cell sorting; HCC, hepatocellular carcinoma; LN, lymph node; N/A, not applicable; OS, overall survival; PBMC, peripheral blood mononuclear cells; TIDC, tumor-infiltrating dendritic cells; TNM, tumor–node–metastasis; WHO, World Health Organization.

  • aNo significance measurement.

  • bReport does not distinguish cytoplasmic from membrane staining.

  • cBecause of positive correlations between protein and mRNA, clinicopathologic correlations in this report were based on mRNA expression data.