Clinicopathologic Analysis of PD-L1 and PD-L2 Expression in Renal Cell Carcinoma: Association with Oncogenic Proteins Status

Shin, Su‐Jin; Jeon, Yoon Kyung; Kim, Pil Jong; Cho, Yong Mee; Koh, Jaemoon; Chung, Doo Hyun; Go, Heounjeong

doi:10.1245/s10434-015-4903-7

Cited by 161 publications

(139 citation statements)

References 28 publications

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“…PD-L2 can bind to the RGMb receptor on the surface of macrophages and other immune cells to promote immune tolerance, although the significance of this observation in cancer is unclear (51). PD-L2 expression has been noted in esophageal adenocarcinoma, breast cancer, and renal cell cancer (35,(52)(53)(54). The significance of PD-L2 expression on epithelial cells is less explored, compared with PD-L1 expression.…”

Section: Discussionmentioning

confidence: 99%

Immune Profiling of Adenoid Cystic Carcinoma: PD-L2 Expression and Associations with Tumor-Infiltrating Lymphocytes

Sridharan

Gjini

Liao

et al. 2016

Cancer Immunology Research

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Adenoid cystic carcinoma (ACC) is among the most lethal salivary gland tumors, with no treatments for metastatic disease that prolong survival. We examined tissue from 28 primary and metastatic ACC deposits obtained from 21 patients for infiltrating immune cells and PD-L1/PD-L2 expression and determined mRNA profiles of over 1,400 oncogenic and immune-related genes. We also assessed the effect of chemoradiation on immune mediators in a patient who had serial biopsies available. Most tumors expressed PD-L2 but had few infiltrating immune cells.Lack of immune-cell infiltrate was associated with expression of genes in the b-catenin/Wnt and PI3K pathways. Additionally, certain transcripts linked to growth and invasion were differentially expressed among primary and metastatic deposits. Chemoradiation appeared to increase CD8 þ effector T cells, decrease regulatory T cells, and promote a systemic humoral response. These data suggest a potential role for PD-L2 inhibition and immune modulation as treatment for patients with ACC.

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Section: Discussionmentioning

confidence: 99%

Immune Profiling of Adenoid Cystic Carcinoma: PD-L2 Expression and Associations with Tumor-Infiltrating Lymphocytes

Sridharan

Gjini

Liao

et al. 2016

Cancer Immunology Research

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“…Recently, different proportions of PD-L1 expression ranging from 9.4 to 56 % PD-L1 positive RCC specimens were reported [15,36,37]. Also, variation in quantitative and qualitative PD-L1 expression was reported among primary and metastatic RCC sites, as well as in dependence of the histological subtype [17,29,30,37]. Krambeck et al evaluated the impact of survivin and PD-L1 expression in 298 ccRCC specimens.…”

Section: Discussionmentioning

confidence: 99%

“…Leite et al [15] published a series of 115 ccRCC specimens wherein 56 % of the specimens showed PD-L1 expression, which in combination with microvascular invasion and a higher nuclear grade is associated with severe prognosis. Recently, going along with findings of the largest analyses of all subtypes of RCC (n = 425), Iacovelli et al performed a meta-analyses suggesting a prognostic role of PD-L1 in RCC [19,37]. Nonetheless, the authors of this analysis underlined the significant heterogeneity of the included studies as potential bias [19].…”

Section: Discussionmentioning

confidence: 99%

Intratumoral expression of programmed death ligand 1 (PD-L1) in patients with clear cell renal cell carcinoma (ccRCC)

et al. 2016

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The immunological checkpoints of programmed death 1 and its ligand (PD-L1) are currently in focus as novel therapeutic targets in renal cell carcinoma (RCC). The aim of this study was to evaluate the prognostic association of PD-L1 expression in clear cell (cc) RCC with clinical parameters, tumor aggressiveness and overall survival (OS). Patients who underwent renal surgery due to RCC between 1994 and 2003 were retrospectively evaluated. Tumor specimens were analyzed for PD-L1 expression by immunohistochemistry. One hundred and seventy-seven ccRCC patients were eligible for analysis, in which 140 (79.1 %) were negative and 37 (20.9 %) were positive for PD-L1 expression. PD-L1 positivity was associated with female gender (p = 0.001), lymph node metastasis (p = 0.004), distant metastasis (p = 0.002), higher AJCC stage (p = 0.004), as well as advanced disease (pT3/4 and/or N+ and/or M1) (p < 0.001). Kaplan-Meier analysis revealed a significantly diminished 5- and 10-year overall survival of 46.7 and 28.3 % for PD-L1(+) compared to PD-L1(-) tumors with 66 and 53.4 % (p = 0.005), respectively. Univariate analysis showed a significant negative association of OS with PD-L1 positivity [p = 0.005; HR: 2 (95 % CI 1.2-3.3)], even though PD-L1 positivity only tends to predict independently the OS using multivariate analyses [p = 0.066; HR: 1.6 (95 % CI 0.98-2.7)]. PD-L1 expression in ccRCC is associated with parameters of aggressiveness, as well as with poor OS, even though PD-L1 status was not identified as a significant independent prognostic parameter. However, further studies in larger cohorts are warranted.

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“…The mean H-score of the five areas was calculated for each case, and mean H-scores were calculated separately for the epithelioid and sarcomatoid components of sRCC. As a quality control measure, two pathologists (FK and KS) manually evaluated PD-L1 tumor positivity, defined as ≥5% tumor cell membrane staining independently 9, 10 . Cases in which the H-score differed from the results of manual evaluation, owing to diffuse infiltration of PD-L1–stained immune and endothelial cells in the tumor area and cytoplasmic PD-L1 staining of tumor cells, were excluded from the study.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, PD-L1 induces epithelial-mesenchymal transition in RCC 7 and sRCC is considered a good example of epithelial-mesenchymal transition both morphologically and immunohistochemically 8 . Two studies evaluated PD-L1 expression in sRCC with clear cell epithelioid component (cc-sRCC) and found it to be significantly higher than in non-sarcomatoid ccRCC 9, 10 . Furthermore, 50% of sRCCs showed co-expression of PD-1/PD-L1, while only 3% of non-sarcomatoid ccRCCs showed PD-1/PD-L1 co-expression 9 .…”

Section: Introductionmentioning

confidence: 99%

Programmed cell death ligand 1 and tumor‐infiltrating lymphocyte status in patients with renal cell carcinoma and sarcomatoid dedifferentiation

Kawakami

Sircar

Rodriguez‐Canales

et al. 2017

Cancer

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Background The immune profile of sarcomatoid renal cell carcinoma (RCC) (sRCC), including PD-L1 and PD-1 status, has not been well characterized. Methods PD-L1, PD-1, CD4, and CD8 immunohistochemical digital analysis was performed on nephrectomy specimens of 118 sRCC and 92 non-sarcomatoid clear cell RCC (ccRCC) patients. Clinical characteristics of the population were compared between sRCC and ccRCC. Overall survival was estimated and was compared between PD-L1–positive and PD-L1–negative groups as well as tumor infiltrating lymphocytes (TIL)–high and TIL–low groups. Results The PD-L1 H-score of sRCC (mean, 3.7; range, 0–192.1) was significantly higher than that of grade 4 ccRCC (P=0.001), and 41.3% of sRCC showed PD-L1 H-score≥10. PD-1–positive cell density was significantly higher in sRCC than in ccRCC within the tumor and at the invasive front. Intratumoral CD8-positive cell density was significantly higher in sRCC than in ccRCC. 41% in sarcomatoid component of sRCC and 8% in epithelioid component of sRCC had an adaptive immune resistance (PD-L1 positive and TIL positive) phenotype, while only 1% in pure epithelioid RCC had Type I phenotype. Conclusions sRCC showed higher PD-L1 expression and higher PD-1 and CD8–positive cell density than grade 4 ccRCC. Our results indicate a notable immunosuppressive environment in sRCC. Despite advances in the treatment of advanced-stage RCC, sRCC still has a poor prognosis. In this work, we describe highly immunosuppressive characteristics of sRCC compared with an appropriate ccRCC control. Our results suggest PD-1/PD-L1 blockade therapy as a potential therapeutic approach for sRCC.

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Clinicopathologic Analysis of PD-L1 and PD-L2 Expression in Renal Cell Carcinoma: Association with Oncogenic Proteins Status

Abstract: PD-L1 and PD-L2 expression predict poor prognosis in CCRCC. Thus, PD-1/PD-L pathway-targeted immunotherapy may be useful for treatment of patients with CCRCC.

Cited by 161 publications

References 28 publications

Immune Profiling of Adenoid Cystic Carcinoma: PD-L2 Expression and Associations with Tumor-Infiltrating Lymphocytes

Immune Profiling of Adenoid Cystic Carcinoma: PD-L2 Expression and Associations with Tumor-Infiltrating Lymphocytes

Intratumoral expression of programmed death ligand 1 (PD-L1) in patients with clear cell renal cell carcinoma (ccRCC)

Programmed cell death ligand 1 and tumor‐infiltrating lymphocyte status in patients with renal cell carcinoma and sarcomatoid dedifferentiation

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