Effect of Platinum-Based Chemotherapy on PD-L1 Expression on Tumor Cells in Non-small Cell Lung Cancer

신정훈,정진행,김세현,이규상,서경진,이지윤,김지원,이정옥,김진원,김유정,이근욱,김지현,방수미,이종석 대한암학회 2019 Cancer Research and Treatment Vol.51 No.3

Purpose Programmed death-1 (PD-1)/PD-1 ligand (PD-L1) axis blockades have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). We assessed the effect of platinum- based chemotherapy on tumor PD-L1 expression and its clinical implications. Materials and Methods We used immunohistochemistry to retrospectively evaluate the percentage of tumor cells with membranous PD-L1 staining (tumor proportion score) in paired tumor specimens obtained before and after platinum-based neoadjuvant chemotherapy (NACT) in 86 patients with NSCLC. We analyzed the correlation between the change in PD-L1 tumor proportion score and clinicopathologic characteristics, response to NACT, and survival. Results The PD-L1 tumor proportion score increased in a significant proportion of patients with NSCLC after platinum-based NACT (Wilcoxon signed-rank test, p=0.002). That pattern was consistent across clinically defined subgroups except for patients with partial response to NACT. Tumors from 26 patients (30.2%) were PD-L1!negative before NACT but PD-L1-positive after NACT, whereas the reverse pattern occurred in six patients (7%) (McNemar’s test, p < 0.001). Increase in PD-L1 tumor proportion score was significantly associated with lack of response to NACT (Fisher exact test, p=0.015). There was a tendency, albeit not statistically significant, for patients with an increase in PD-L1 tumor proportion score to have shorter survival. Conclusion Tumor PD-L1 expression increased after platinum-based NACT in a significant proportion of patients with NSCLC. Increase in tumor PD-L1 expression may predict poor clinical outcome.

Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma

Lee, B.S.,Park, D.I.,Lee, D.H.,Lee, J.E.,Yeo, M.k.,Park, Y.H.,Lim, D.S.,Choi, W.,Lee, D.H.,Yoo, G.,Kim, H.b.,Kang, D.,Moon, J.Y.,Jung, S.S.,Kim, J.O.,Cho, S.Y.,Park, H.S.,Chung, C. Academic Press 2017 Biochemical and biophysical research communication Vol. No.

Developments of EGFR-TKI and immunotherapy targeting the PD1/PD-L1 pathway are considered most important medical breakthroughs in lung cancer treatment. Nowadays, 3rd generation EGFR TKI is widely used for T790M positive 1st and 2nd EGFR-TKI resistant lung cancer patients. Immunotherapy is powerful option for lung cancer patients without drug targets and chemotherapy resistant patients. It also has changed the concept of conventional anti-cancer therapy in the point of regulating tumor microenvironment. There are many studies linking these two important pathways. Recent studies demonstrated that PD-L1 expression is significantly correlated to the mutation status of EGFR, and activation of EGFR signaling can also induce the expression of PD-L1. However, the real linker between PD-L1 and EGFR signaling remains to be revealed. Our previous study revealed that the Hippo pathway effector YAP confers EGFR-TKI resistance in lung adenocarcinoma, and inhibition of YAP restores sensitivity to EGFR-TKIs. Thus, we examined whether PD-L1 is relevant, in terms of conferring EGFR-TKI resistance and whether YAP directly regulates the expression of PD-L1 in this context. First, we compared the expression levels of PD-L1 and YAP between EGFR-TKI-resistant PC9 cells and the parental PC9 adenocarcinoma cells. The expression levels of both YAP and PD-L1 were markedly higher in the EGFR-TKI-resistant cells compared to the parental cells, suggesting differential expression pattern between two cell types. YAP knockdown significantly decreased the expression of PD-L1 in the EGFR-TKI-resistant cells, while YAP overexpression increased the expression of PD-L1 in the parental PC9 cells. Then, our results revealed that YAP regulates the transcription of PD-L1, and the YAP/TEAD complex binds to the PD-L1 promoter. Surprisingly, knockdown of PD-L1 was sufficient to decrease cell proliferation and wound healing in the EGFR-TKI-resistant PC9 cells. These data suggest a PD1-independent oncogenic function of PD-L1. The Hippo effector YAP plays a crucial role in linking the PD-L1 and EGFR-TKI resistance by directly regulating the expression of PD-L1 in lung cancer. Targeting PD-L1 directly or via YAP could provide an effective therapeutic strategy for EGFR-TKI-resistant lung adenocarcinoma.

A Novel Anti-PD-L1 Antibody Exhibits Antitumor Eff ects on Multiple Myeloma in Murine Models via Antibody-Dependent Cellular Cytotoxicity

( Jae-hee Ahn ),( Byung-hyun Lee ),( Seong-eun Kim ),( Bo-eun Kwon ),( Hyunjin Jeong ),( Jong Rip Choi ),( Min Jung Kim ),( Yong Park ),( Byung Soo Kim ),( Dae Hee Kim ),( Hyun-jeong Ko ) 한국응용약물학회 2021 Biomolecules & Therapeutics(구 응용약물학회지) Vol.29 No.2

Multiple myeloma is a malignant cancer of plasma cells. Despite recent progress with immunomodulatory drugs and proteasome inhibitors, it remains an incurable disease that requires other strategies to overcome its recurrence and non-response. Based on the high expression levels of programmed death-ligand 1 (PD-L1) in human multiple myeloma isolated from bone marrow and the murine myeloma cell lines, NS-1 and MOPC-315, we propose PD-L1 molecule as a target of anti-multiple myeloma therapy. We developed a novel anti-PD-L1 antibody containing a murine immunoglobulin G subclass 2a (IgG2a) fragment crystallizable (Fc) domain that can induce antibody-dependent cellular cytotoxicity. The newly developed anti-PD-L1 antibody showed significant antitumor effects against multiple myeloma in mice subcutaneously, intraperitoneally, or intravenously inoculated with NS-1 and MOPC-315 cells. The anti-PD-L1 effects on multiple myeloma may be related to a decrease in the immunosuppressive myeloidderived suppressor cells (MDSCs), but there were no changes in the splenic MDSCs after combined treatment with lenalidomide and the anti-PD-L1 antibody. Interestingly, the newly developed anti-PD-L1 antibody can induce antibody-dependent cellular cytotoxicity in the myeloma cells, which differs from the existing anti-PD-L1 antibodies. Collectively, we have developed a new anti-PDL1 antibody that binds to mouse and human PD-L1 and demonstrated the antitumor effects of the antibody in several syngeneic murine myeloma models. Thus, PD-L1 is a promising target to treat multiple myeloma, and the novel anti-PD-L1 antibody may be an effective anti-myeloma drug via antibody-dependent cellular cytotoxicity effects.

PD-L1 expression correlated with p53 expression in oral squamous cell carcinoma

Tojyo, Itaru,Shintani, Yukari,Nakanishi, Takashi,Okamoto, Kenjiro,Hiraishi, Yukihiro,Fujita, Shigeyuki,Enaka, Mayu,Sato, Fuyuki,Muragaki, Yasuteru Korean Association of Maxillofacial Plastic and Re 2019 Maxillofacial Plastic Reconstructive Surgery Vol.41 No.-

Background: Programmed cell death ligand 1 (PD-L1) is an immune checkpoint molecule that attenuates the immune response. PD-L1 contributes to failed antitumor immunity; thereby, blockade of PD-L1 with monoclonal antibody enhances the immune response. Recently, it was reported that PD-L1 was regulated by protein 53 (p53). Besides, cytokeratin 17 (CK17) is thought to be a diagnostic marker of oral squamous cell carcinoma (OSCC). Our aim was to evaluate the correlation between the immunohistochemical expression of PD-L1, p53 and CK17 with clinicopathological characteristics and disease-specific survival in patients with OSCC. Methods: A total of 48 patients with OSCC were included in this study. Immunohistochemical staining was performed to evaluate the correlation among the expressions of PD-L1, p53 and CK17, and furthermore the correlation among various clinicopathological factors, PD-L1, p53 and CK17. Results: The positive rate of p53, CK17, PD-L1 (tumor cells) and PD-L1 (tumor-infiltrating lymphocytes) was 63.2%, 91.7%, 48.9% and 57.1%. A statistically significant correlation between p53 expression and T stage and TNM stage (p = 0.049, p = 0.03, respectively) was observed. Also, a statistically significant correlation between p53 and PD-L1 (TCs) expression (p = 0.0009) was observed. Five-year disease-specific survival rate was not significantly correlated with gender, TNM stage, p53 expression, PD-L1 expression and CK17 expression. Conclusion: The expression of p53 and PD-L1 shows significantly positive correlation in oral squamous cell carcinoma in tumor cells. Also, a significant correlation between p53 expression and T stage and TNM stage was observed. No other significant correlation between PD-L1 staining or CK17 and clinical or pathologic characteristics was identified.

PD-L1 (SP142) Expression in Primary and Recurrent/Metastatic Triple-Negative Breast Cancers and Its Clinicopathological Significance

한은경,우지원,서경진,김세현,김지현,박소연 대한암학회 2024 Cancer Research and Treatment Vol.56 No.2

Purpose The programmed death-ligand 1 (PD-L1) SP142 assay identifies patients with triple-negative breast cancer (TNBC) who are most likely to respond to the anti–PD-L1 agent atezolizumab. We aimed to compare PD-L1 (SP142) expression between primary and recurrent/metastatic TNBCs and elucidate the clinicopathological features associated with its expression. Materials and Methods Primary and recurrent/metastatic TNBCs tested with PD-L1 (SP142) were collected, and clinicopathological information of these cases was obtained through a review of slides and medical records. Results PD-L1 (SP142) positivity was observed in 50.9% (144/283) of primary tumors and 37.8% (31/82) of recurrent/metastatic TNBCs with a significant difference. Recurrent or metastatic sites were associated with PD-L1 positivity, with high PD-L1 positivity in the lung, breast, and soft tissues, and low positivity in the bone, skin, liver, and brain. When comparing PD-L1 expression between primary and matched recurrent/metastatic TNBCs using 55 paired samples, 20 cases (36.4%) showed discordance; 10 cases revealed positive conversion, and another 10 cases revealed negative conversion during metastatic progression. In primary TNBCs, PD-L1 expression was associated with a higher histologic grade, lower T category, pushing border, and higher tumor-infiltrating lymphocyte infiltration. In survival analyses, PD-L1 positivity, especially high positivity, was found to be associated with favorable prognosis of patients. Conclusion PD-L1 (SP142) expression was lower in recurrent/metastatic TNBCs, and substantial cases showed discordance in its expression between primary and recurrent/metastatic sites, suggesting that multiple sites may need to be tested for PD-L1 (SP142) when considering atezolizumab therapy. PD-L1 (SP142)–positive TNBCs seems to be associated with favorable clinical outcomes.

Expression of PD-L1 in different progression forms of cutaneous squamous cell carcinoma, keratoacanthoma, and basal cell carcinoma

( Moon Hyung You ),( Joon Goon Kim ),( Yeon Woong Kim ),( Dong Hoon Shin ),( Jong Soo Choi ) 대한피부과학회 2017 대한피부과학회 학술발표대회집 Vol.69 No.2

Background: Programmed cell death ligand 1 (PD-L1) play a major role in the immune responses of a variety of cancers. Recently, several studies revealed that PD-L1 is differently expressed in a proportion of non-melanoma skin cancer. PD-1 inhibitors have shown durable responses in various tumor entities. The membranous PD-L1 expression of tumour cells has been worked out as biomarker to predict the response to PD-1 antibody treatment in several cancers. The expression of PD-L1 in cutaneous malignancy has not been described in Korea yet. Objectives: To investigate the expression of PD-L1 in different progression forms of cutaneous squamous cell carcinoma (cSCC), keratoacanthoma (KA), and basal cell carcinoma (BCC). Methods: We performed immunohistochemical staining of 20 KA, 20 actinic keratoses (AK), 20 Bowen´s diseases (BD), 20 cSCC, and 20 BCC. Cases were selected from the patients who had visited the department of dermatology of the Yeungnam university medical center from 2001 to 2017. The expression patterns were assessed using the semi-quantitative staining intensity evaluation. Cases demonstrating at least 1+ of PD-L1 were considered positive. Results: PD-L1 expression of tumor cells was 25.0% (5/20) for cSCC. In AK, BD, KA, and BCC, there was no detectable immunoreactivity for PD-L1. Conclusion: cSCC exhibit PD-L1 expression in a fourth of cases, indicating that PD-L1 inhibitors might be helpful in some of the patients with an inoperable or metastatic cSCC.

Porcine PD-L1: cloning, characterization, and implications during xenotransplantation

Jeon, Dae-Hyun,Oh, Keunhee,Oh, Byoung C.,Nam, Dong H.,Kim, Chi H.,Park, Hyung-Bae,Cho, Jaejin,Lee, Jeong R.,Lee, Dong-Sup,Lee, Gene Blackwell Publishing Ltd 2007 Xenotransplantation Vol.14 No.3

<P>Abstract: Background: </P><P>Effective intervention achieved by manipulating cell-mediated xenogeneic immune responses would critically increase the clinical feasibility of xenotransplantation as immediate hyperacute rejections become controllable through genetic modulations of donor organs. Endogenous negative regulatory signals like the programmed death 1 (PD-1)-programmed death ligand 1 (PD-L1) system are candidate targets for the control of cell-mediated xenogeneic immune response.</P><P>Methods: </P><P>A porcine PD-L1 molecule was cloned using RACE (rapid amplification of cDNA ends) technology based on the human PD-L1 sequence. The functional effects of cloned porcine PD-L1 were tested on human CD4<SUP>+</SUP> T cell activation using porcine PD-L1-transfected bystander cells. Cellular proliferation was monitored by [<SUP>3</SUP>H] thymidine incorporation, and human T cell apoptosis was measured by flow cytometry.</P><P>Results: </P><P>Porcine PD-L1 (GenBank accession number AY837780) was found to have 73.8% sequence homology with human PD-L1 and to contain two immunoglobulin domains in its extracellular region. Moreover, porcine PD-L1 expressed on Chinese hamster ovary (CHO) cells inhibited human CD4<SUP>+</SUP> T cell proliferation stimulated with anti-CD3 only or anti-CD3 plus anti-CD28. Percentages of apoptotic activated human T cells increased by over 30% in the presence of porcine PD-L1/CHO cells, and the addition of recombinant human PD-1-Fc fusion proteins during human T cell activation reversed the inhibitory effects of porcine PD-L1.</P><P>Conclusions: </P><P>Cloned porcine PD-L1 showed high sequence homology with human PD-L1 and a similar molecular structure. Moreover, porcine PD-L1 inhibited human CD4<SUP>+</SUP> T cell activation in human PD-1-dependent manner, and this involved activated T cell apoptosis. The authors suggest that PD-1-PD-L1 might play an important endogenous immune regulatory role during xenogeneic transplantation, and that the effective application of this system would improve transplanted xenogeneic organ survival.</P>

피부 편평세포암종에서 PD-L1의 면역조직화학적 발현과 전이 위험과의 연관성

유문형 ( Moonhyung You ),신동훈 ( Donghoon Shin ),최종수 ( Jongsoo Choi ),배영경 ( Youngkyung Bae ),이지민 ( Jihmin Lee ) 대한피부과학회 2018 대한피부과학회지 Vol.56 No.7

Background: Programmed cell death ligand 1 (PD-L1) plays a major role in the immune responses of a variety of cancers. Recently, several studies revealed that PD-L1 is differently expressed in some cases of non-melanoma skin cancer. The expression of PD-L1 in cutaneous squamous cell carcinoma has not yet been described in Korea. Objective: To investigate the expression of PD-L1 in cutaneous squamous cell carcinoma and its association with variable clinicopathological factors. Methods: We performed immunohistochemical staining of 52 cutaneous cell carcinoma cases, including 28 high-risk cases and 24 low-risk cases. Cases were selected from patients who had visited the department of dermatology of our hospital from 2001 to 2017. The expression patterns were assessed using the H-score. Cases demonstrating at least 1+ of PD-L1 in more than 1% of tumor cells were considered positive. Results: PD-L1 expression of tumor cells was 19.2% (10/52) for all cases, 0.0% (0/24) for the low-risk group, and 35.7% (10/28) for the high-risk group. PD-L1 positive cutaneous squamous cell carcinoma cases showed a significantly higher proportion of large tumors and tumors with deep invasion and a higher lymphatic metastasis rate when compared to PD-L1 negative cutaneous squamous cell carcinoma cases. Conclusion: Our study shows that cutaneous squamous cell carcinoma exhibits PD-L1 expression in 19.2% of cases. PD-L1 positive tumors are associated with high-risk cases of cutaneous squamous cell carcinoma, which may help guide the choice of therapeutic strategy. (Korean J Dermatol 2018;56(7):415∼420)

Correlation of PD-L1 Expression Tested by 22C3 and SP263 in Non-Small Cell Lung Cancer and Its Prognostic Effect on EGFR Mutation-Positive Lung Adenocarcinoma

( Taehee Kim ),( Yoon Jin Cha ),( Yoon Soo Chang ) 대한결핵 및 호흡기학회 2020 Tuberculosis and Respiratory Diseases Vol.83 No.1

Background: Programmed death-ligand 1 (PD-L1) expression is tested by immunohistochemistry (IHC)―22C3, SP263, and SP142. The aim of this study is to evaluate the correlation among the three methods of PD-L1 IHC in non-small cell lung cancer (NSCLC) and clinical significance of PD-L1 expression in lung adenocarcinoma with an epidermal growth factor receptor (EGFR)-tyrosine kinase domain mutation. Methods: The results of 230 patients who were pathologically confirmed as having NSCLC; tested using PD-L1 IHC 22C3, SP263, and SP142 methods; and evaluated via the peptide nucleic acid clamping method to confirm EGFR mutation, were analyzed in this study. Results: 164 patients underwent both the SP263 and 22C3 tests. There was a significant positive correlation between the outcomes of the two tests (Spearman correlation coefficient=0.912, p<0.001), with a derived regression equation as follows: 22C3=15.2+0.884×SP263 (R²=0.792, p<0.001). There was no relationship between the expression of PD-L1 and clinical parameters, including EGFR-tyrosine kinase inhibitor (TKI) mutation. The PD-L1 expression in patients treated with EGFR-TKI yielded a 2-month-shorter progression period than that in the PD-L1-negative group. However, this did not reach statistical significance (PD-L1<1% vs. PD-L1≥1%, 10 months vs. 8 months). Conclusion: The results of the 22C3 and those of SP263 methods were in good correlation with one another. Since the PD-L1 expression is not influenced by the EGFR mutation, it is necessary to perform a PD-L1 test to set the treatment direction in the patients with EGFR-mutant NSCLC.

F-154 Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma

정재욱,박세연,강다현,박동일,문재영,이정은,정성수,박희선,김주옥 대한결핵 및 호흡기학회 2017 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.124 No.-

Immunotherapy is powerful option for lung cancer patients without drug targets and chemotherapy resistant patients. It also has changed the concept of conventional anti-cancer therapy in the point of regulating tumor microenvironment. Our previous study revealed that the Hippo pathway effector YAP confers EGFR-TKI resistance in lung adenocarcinoma, and inhibition of YAP restores sensitivity to EGFR-TKIs. In this study, we examined whether PD-L1 is relevant in terms of conferring EGFR-TKI resistance and whether YAP directly regulates the expression of PD-L1. First, we compared the expression levels of PD-L1 and YAP between EGFR-TKI-resistant PC9 cells and the parental PC9 adenocarcinoma cells. The expression levels of both YAP and PD-L1 were markedly higher in the EGFR-TKI-resistant cells compared to the parental cells. YAP knockdown significantly decreased the expression of PD-L1 in the EGFR-TKI-resistant cells, while YAP overexpression increased the expression of PD-L1 in the parental PC9 cells. Then, our results revealed that YAP regulates the transcription of PD-L1, and the YAP/TEAD complex binds to the PD-L1 promoter. Surprisingly, knockdown of PD-L1 was sufficient to decrease cell proliferation and wound healing in the EGFR-TKI-resistant PC9 cells. These data suggest a PD1-independent oncogenic function of PD-L1. The Hippo effector YAP plays a crucial role in linking the PD-L1 and EGFR-TKI resistance by directly regulating the expression of PD-L1 in lung cancer. Targeting PD-L1 directly or via YAP could provide an effective therapeutic strategy for lung adenocarcinoma.