Thoracic SMARCA4-deficient undifferentiated tumor-pathological diagnosis and combined immune checkpoint inhibitor treatment / 北京大学学报(医学版)

We explored clinicopathological features and treatment strategies for thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT). Thoracic SMARCA4-UT is a new entity recently acknowledged in the 2021 edition of World Health Organization Classification of Thoracic Tumors, and doctors are relatively unfamiliar with its diagnosis, treatment, and prognosis. Taking a case of SMARCA4-UT treated in Peking University First Hospital as an example, this multi-disciplinary discussion covered several hot issues on diagnosing and treating thoracic SMARCA4-UT, including histological features, immu- nohistochemical and molecular phenotype, immune checkpoint inhibitor (ICI) therapy, and pathological assessment of neoadjuvant therapy response. The patient was an older man with a long history of smoking and was admitted due to a rapidly progressing solid tumor in the lower lobe of the right lung. Histologically, tumor cells were epithelioid, undifferentiated, diffusely positive for CD34, and partially positive for SALL4.The expression of BRG1 protein encoded by SMARCA4 gene was lost in all of tumor cells, and next-generation sequencing(NGS)confirmed SMARCA4 gene mutation (c.2196T>G, p.Y732Ter). The pathological diagnosis reached as thoracic SMARCA4-UT, and the preoperative TNM stage was T1N2M0 (ⅢA). Tumor proportion score (TPS) detected by immunohistochemistry of programmed cell death 1-ligand 1 (PD-L1, clone SP263) was 2%. Tumor mutation burden (TMB) detected by NGS of 1 021 genes was 16. 3/Mb. Microsatellite detection showed the tumor was microsatellite stable (MSS). Neo-adjuvant therapy was implemented with the combined regimen of chemotherapy and ICI. Right lower lobectomy was performed through thoracoscopy after the two weeks' neoadjuvant. The pathologic assessment of lung tumor specimens after neoadjuvant therapy revealed a complete pathological response (CPR). The post-neoadjuvant tumor TNM stage was ypT0N0M0. Then, five cycles of adjuvant therapy were completed. Until October 2022, neither tumor recurrence nor metastasis was detected, and minimal residual disease (MRD) detection was negative. At present, it is believed that if BRG1 immunohistochemical staining is negative, regardless of whether SMARCA4 gene mutation is detected, it should be classified as SMARCA4-deficient tumors. SMARCA4-deficient tumors include a variety of carcinomas and sarcomas. The essential criteria for diagnosing SMARCA4-UT includes loss of BRG1 expression, speci-fic histological morphology, and exclude other common thoracic malignant tumors with SMARCA4-deficiency, such as squamous cell carcinoma, adenocarcinoma and large cell carcinoma. SMARCA4-UT is a very aggressive malignant tumor with a poor prognosis. It has almost no targeted therapy mutations, and little response to chemotherapy, but ICI is currently the only effective drug. The successful diagnosis and treatment for this case of SMARCA4-UT should enlighten significance for various kinds of SMARCA4-deficient tumors.

Consistency comparison of programmed cell death 1-ligand 1 in different immuno-histochemical staining methods / 北京大学学报(医学版)

OBJECTIVE@#To compare the consistency of programmed cell death 1-ligand 1 (PD-L1, clone E1L3N, 22C3, SP263) in different immunohistochemical staining methods.@*METHODS@#The first step was to select the optimal process: The PD-L1(clone E1L3N) antibody recommended process, self-built process ①, self-built process ② and self-built process ③ were used to perform immunohistochemical staining in 5 cases of tonsil tissue. The quality of all slides was scored by expert pathologists (0-6 points). The process with the highest score was selected. The second step was to compare the consistency between the optimal procedure and the two standard procedures. Thirty-two cases of lung non-small cell carcinoma diagnosed by pathology in Peking University First Hospital in the past two years were randomly selected. The 32 cases were stained in parallel with the SP263 and 22C3 standard procedures, and all stained slides were scored by specialized pathologists for tumor proportion score (TPS). The scoring results were grouped according to < 1%, ≥1% to < 10%, ≥10% to < 50%, and ≥50%. The consistency of PD-L1 detection antibody clone E1L3N and 22C3, E1L3N and SP263 staining results was analyzed.@*RESULTS@#Tonsil stained slides scores (0-6 points) were as follows: The recommended protocol was 5, 5, 5, 5 and 5. The self-built process ① was 5, 6, 6, 5 and 6. The self-built process ② was 4, 4, 4, 4 and 4.The self-built process ③ was 3, 3, 3, 3 and 3. The self-built process ① was the best with the highest score. The TPSs of 32 non small cell lung carcinoma (NSCLC) cases were as follows: Of self-built process ①, 6 cases were lower than 1%, 5 cases were from 1% to 10%, 10 cases were from 10% to 50%, and 11 cases were higher than 50%; of 22C3 standard procedure, 5 cases were lower than 1%, 3 cases were from 1% to 10%, 13 cases were from 10% to 50%, 11 cases were higher than 50%; of SP263 standard procedure, 7 cases were lower than 1%, 4 cases were from 1% to 10%, 11 cases were from 10% to 50%, 10 cases were higher than 50%. The results of the consistency test were as follows: The κ value for self-built process ① and 22C3 standard procedure was 0.736 (P < 0.001), the agreement was good; the κ value for self-built process ① and SP263 standard procedure was 0.914 (P < 0.001), the agreement was very good.@*CONCLUSION@#The immunostaining using PD-L1(E1L3N) with validated self-built staining protocol ① by Ventana Benchmark GX platform can obtain high quality of slides, and the TPSs based on these slides are in good agreement with 22C3 and SP263 standard procedures.

Supervivencia extendida con pembrolizumab en un paciente con cáncer de pulmón no microcítico estadio IV: Reporte de caso / Extendedsurvival with pembrolizumab in a patient with stage IV non-small cell lung cancer:A case report

Introducción:La inmunoterapia con pembrolizumab ha mejorado el pronóstico del cáncer de pulmón metastásico. En el presente caso se presenta la supervivencia extendidad y evolución de un paciente específico.Caso clínico:Hombre de 66 años, fumador. Diagnosticado de masa pulmonar en lóbulo infe-rior izquierdo de dimensiones 9 x 8 cm, con metástasis supra e infratentoriales intraaxiliares. Taller diagnóstico: Establecida como neoplasia de pulmón en estadio IVc, se comprobó el estado de PDL1 que positivo en un 80 % de la muestra de masa pulmonar. Debuta con me-tástasis cerebrales.Evolución: Se inció inmunoterapia con Pembrolizumab, el cual se mantubo hasta la presencia de un efecto secundario atribuido al pembrolizumab, cumpliendo 30meses de supervivencia hasta el cierre de esta observación no se reportó la muerte del paciente.Conclusiones:En el presente reporte, la determinación del biomarcador histológico PDL1 po-sitivo en cáncer de pulmón ayudo a prescribir un tratamiento con inmunoterpia dirigida, lo que demostró aumentar la supervivencia más allá que el tratamiento convencional con quimiote-rapia

Introduction: Immunotherapy with pembrolizumab has improved the prognosis of metastatic lung cancer. A specific patient's extended survival and evolution is presented in the present case.Clinical case: 66-year-old man, smoker. Diagnosed with a lung mass in the left lower lobe measuring 9 x 8 cm, with supra and infratentorial intra-axial metastases.Diagnostic workshop: To establisha stage IVc lung neoplasm, 80% of the lung mass sample was confirmed to be positive for PDL1.Evolution: Immunotherapy was started with Pembrolizumab, which was maintained until the presence of a side effect attributed to pembrolizumab, completing 30 months of survival until the closure of this observation, the patient's death was not reported.Conclusions: In the present report, the determination of the positive histological biomarker PDL1 in lung cancer helped prescribe treatment with targeted immunotherapy, which was shown to increase survival beyond conventional treatment with chemotherapy

Study on the mechanism of VEGF inducing tolerogenic dendritic cells in oral squamous cell carcinoma / 口腔医学

Objective@#To investigate the mechanism of vascular endothelial growth factor(VEGF) inducing tolerogenic dendritic cells(DCs) in oral squamous cell carcinoma (OSCC).@*Methods@#The DCs were divided into four groups: Control group (DC), VEGF group (VEGF added into DC), Co-culture group (DC co-cultured with SCC7) and Anti-VEGF group (anti-VEGF antibody added into DC co-cultured with SCC7). Flow cytometry (FCM) was used to detect DC surface markers. To detect the effect of DC on proliferation activity of T lymphocyte, the experiment included five groups: Nc group (T lymphocyte), Control group (T lymphocyte added into DC), VEGF group (T lymphocyte + DC + VEGF), Co-culture group (T lymphocyte + DC + supernatant of SCC7) and Anti-VEGF group (T lymphocyte + DC + supernatant of SCC7 + anti-VEGF antibody). Subsequently, the mixed lymphocyte reaction(MLR) was conducted. The expression levels of indole-2, 3-doxygenase(IDO)and programmed cell death 1 ligand 1(PD-L1)in DC were detected by western blot, real time PCR and FCM respectively. For the cytotoxic lymphocyte (CTL) assay, SCC7 cells and CTLs were mixed and CTL-mediated SCC7 cells cytotoxicity was tested. The experiment included four groups: Control group (T lymphocyte + DC), IDO inhibition group (T lymphocyte + DC + IDO inhibitor), Anti-PD-L1 antibody group (T lymphocyte + DC + anti-PD-L1 antibody) and Combination group (T lymphocyte + DC + IDO inhibitor + anti-PD-L1 antibody). The SCC7 tumor-bearing mice treated with IDO inhibitor and the anti-PD-L1 antibody were sacrificed and the tumor inhibition rate and the spleen index were determined. @*Results@#Compared with Control group, exogenous VEGF or SCC7 co-culture inhibited the relative number of DC expressing CD11C, CD80, CD86, CD40 and MHC Ⅱ. The positive DCs were increased in the Anti-VEGF group compared with VEGF or Co-culture group. In VEGF or Co-culture group, the number of T cells stimulated by SCC7-pulsed DCs was decreased compared with Control group. However, the ability of Anti-VEGF group to induce T cell proliferation was significantly increased compared with VEGF or Co-culture group. Significantly increased expression of IDO and PD-L1 were observed in VEGF and Co-culture group. However, this was partially reversed by addition of anti-VEGF antibody into the co-culture system. Compared with Control group, the expressions of CD11C and CD86 in DC in both the IDO inhibition group and Anti-PD-L1 antibody group were increased, and were significantly higher in the Combination group compared with the single drug groups. The similar results were exhibited in MLR and CTL assay. In vivo, the results revealed that the tumors obtained from the mice in three experimental groups were smaller than those in the control group. Furthermore, the tumor volume of the Combination group was the smallest. The spleen index of each group was calculated and the results showed the spleen index of the three experimental groups was significantly higher than that of Control group.@*Conclusion@#VEGF in OSCC micro-environment inhibits the maturation and function of DC that are transformed into tolerogenic DC by high expression of IDO and PD-L1.

Posttranslational Modifications of PD-L1 and Its Prospect Application in Immunotherapy / 中国生物化学与分子生物学报

PD-L1 (programmed cell death 1 ligand 1 ) is an immunosuppressive ligand which mainly expressed on tumor cells, inhibiting the activation of T lymphocytes through binding with PD-1 (programmed cell death protein 1), thus leading to immune escape.PD-1/PD-L1 immune checkpoint blockade therapy, which established based on the above mechanism, gained success in the clinical treatment of solid tumors.Various kinds of PD-L1 posttranslational modifications were identified following the in-depth studies of PD-L1, including glycosylation, phosphorylation, ubiquitination, palmitoylation, et al.Meanwhile, multiple studies indicated that posttranslational modifications governs PD-LI-mediated immune escape through regulating the protein stability and physiological functions of PD-L1, which makes posttranslational modifications of PD-L1 turns into a new "entry" point of PD-L1 studies.Drugs targeting posttranslational modifications of PD-L1 exhibited favorable applicational prospects in immunotherapy at the same time.Regulating PD-L1-mediated immune escape through intervening PD-L1 posttranslational modifications becomes a new strategy for improving the efficacy of immunotherapy.In this review, we summarized the posttranslational modifications of PD-L1 and its applicational prospects in immunotherapy, hoping to provide theoretical supports for future studies focused on PD-L1.

Systematic Review of Cost-utility Analysis Methodology for PD- 1/PD-L1 Inhibitors in the Treatment of Non- small Cell Lung Cancer / 中国药房

OBJECTIVE：To provide reference for impro ving the quality of programmed cell death protein 1 （PD-1）/ programmed cell death 1 ligand（PD-L1）inhibitors in the treatment of non-small cell lung cancer related pharmacoeconomic studies in China. METHODS ：Retrieved from Embase ，PubMed，Medline，Cochrane Library ，CNKI，Wanfang database ，VIP and other Chinese and English database ，cost-utility studies about PD- 1/PD-L1 inhibitors in the treatment of non-small cell lung cancer published during Jan. 2016-Jan. 2021 were collected. The data of the included studies were extracted. After the quality of the included studies was evaluated by using the Consolidated Health Economic Evaluation Reporting Standards list ，the relevant data were summarized and compared from the aspects of model framework ，model parameters and uncertainty analysis. RESULTS & CONCLUSIONS：A total of 17 studies were finally included ，the overall quality of them was high but the differences in methodology were great. Markov model or partition survival model based on three states was adopted for 16 studies. The time horizon ranged from 5 years to lifetime ；the cycle length ranged from 1 week to 6 weeks. A total of 8 studies used the standard parameter distribution method for parameter fitting ，and 7 studies additionally adopted other parameters estimation methods as KM curves or spline models. Eleven studies performed the validation of model extrapolation. All studies considered the direct medical costs and reported the incremental cost-effectiveness ratio using quality-adjusted life years as the health outcome. Sixteen studies conducted the deterministic sensitivity analysis and probabilistic sensitivity analysis to improve the stability of the model. It is suggested that studies should keep the integrity of the report ； format，choose the appropriate positive comparators ，selectthe health economic model and construct reasonable assumptions according to the available data format ， use Cholesky decomposition to explore the uncertainty of the parameter fitting ， perform the validation of extrapolation combined with external data and use the appropriate indirect comparison in the absence of the head-to-head clinical trials to improve the quality of related pharmacoeconomic studies in China.

Research advances of nanoknife ablation combined with programmed death-1/programmed death ligand-1 in treatment of pancreatic cancer and relative immunological mechanisms / 中国介入影像与治疗学

Although the special tumor microenvironment of pancreatic cancer is not conducive to immunotherapy, nanoknife ablation can partial reverse immunosuppression, therefore is the only way of ablation for pancreatic cancer. Results of animal studies showed that the treatment of pancreatic cancer with nanoknife ablation combined with programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) might prolong the survival time. The research advances of the mechanisms of nanoknife ablation combined with PD-1/PD-L1 in treatment of pancreatic cancer and the relative immunological mechanisms were reviewed in this article.

Peripheral blood immune cell-based biomarkers in anti-PD-1/PD-L1 therapy

Immune checkpoint blockade targeting PD-1 and PD-L1 has resulted in unprecedented clinical benefit for cancer patients. Anti-PD-1/PD-L1 therapy has become the standard treatment for diverse cancer types as monotherapy or in combination with other anti-cancer therapies, and its indications are expanding. However, many patients do not benefit from anti-PD-1/PD-L1 therapy due to primary and/or acquired resistance, which is a major obstacle to broadening the clinical applicability of anti-PD-1/PD-L1 therapy. In addition, hyperprogressive disease, an acceleration of tumor growth following anti-PD-1/PD-L1 therapy, has been proposed as a new response pattern associated with deleterious prognosis. Anti-PD-1/PD-L1 therapy can also cause a unique pattern of adverse events termed immune-related adverse events, sometimes leading to treatment discontinuation and fatal outcomes. Investigations have been carried out to predict and monitor treatment outcomes using peripheral blood as an alternative to tissue biopsy. This review summarizes recent studies utilizing peripheral blood immune cells to predict various outcomes in cancer patients treated with anti-PD-1/PD-L1 therapy.

Early Experiences with Nivolumab in Patients with Metastatic Renal Cell Carcinoma and Failed Target Therapy

PURPOSE: The efficacy of nivolumab in metastatic renal cell carcinoma (mRCC) has been proven. However, the nivolumab experience in Korean patients with mRCC is still poorly reported. We report initial experiences with the efficacy and safety of nivolumab in patients with mRCC. MATERIALS AND METHODS: We retrospectively reviewed records for 25 patients with mRCC who had failed targeted therapy and were treated by nivolumab (2 mg/kg, every 2 weeks) at a single institution. The primary endpoint was objective response rate (ORR), and secondary endpoints were progression-free survival (PFS), safety profiles, and ORR in a programmed cell death receptor ligand 1 (PD-L1) expression subgroup. RESULTS: The median age was 60 years and 16 patients (64%) were male. Objective responses were achieved in 8 patients (32.0%) (complete response, 1; partial response, 7). Median PFS was 3.0 months (95% confidence interval, 1.46–4.53). Treatment-related adverse events (AEs) of any grade were observed in 19 patients (76.0%) with 6 (24.0%) experiencing grade 3 to 4 treatment-related AEs. In subgroups by PD-L1 expression levels classified as 1% or greater and less than 1%, ORR was 50% and 0%, respectively. CONCLUSIONS: This study showed the efficacy and safety of initial experiences with nivolumab in Korean patients with mRCC who had failed targeted therapy. Our results were comparable to recent clinical trials on nivolumab in mRCC.

Preparation of fusion protein of PD-L1 single-chain antibody and verification of its antitumor activity / 中国免疫学杂志

Objective: Using yeast surface presentation technology, secreted anti-PD-L1 single-chain antibody fragment ( sc Fv), then purify the sc Fv that specifically binds PD-L1 antigen. The sc Fv antibody gene sequence was synthesized based on the single chain antibody gene sequence. We express this sc Fv-mFc protein by using p Fuse eukaryotic expression vector to study its affinity and in vitro and in vivo inhibition of lung adenocarcinoma cells ( A549). Methods: Recombinant plasmid p Fuse-scFv was constructed by gene engineering. The recombinant plasmid p Fuse-scFv was transfected into 293 F ( human embryonic kidney cells) and cultured in serum-free Pro293 a-CDM for 72 hours, then the fusion protein was collected, and use the Rapid Protein Liquid Phase Separation and Purification System to purify the sc Fv-mFc fusion protein. Then the fusion protein and the tumor cells were detected by immunohistochemistry; the affinity of fusion protein and tumor cells was analyzed by flow cytometry; ADCC was used to determine the proliferation of tumor cells in vitro. The nude mice inoculated with lung adenocarcinoma cells, and use the fusion protein to verify its anti-tumor effect in vivo. Results: sc Fv-mFc fusion protein was secreted into serum-free culture medium by recombinant plasmid transfection into the 293 F cells; immunohistochemistry and flow cytometry showed that the fusion protein was highly expressed with the surface of PD-L1 protein;ADCC showed that the fusion protein inhibited the proliferation of tumor cells in vitro; the results of tumor-bearing mice showed that the fusion protein inhibited the growth of the tumor. At the dose of 5 mg/kg, The tumor volume growth rate decreased from 14. 90％ to3. 72％, the two independent samples t test P＜0. 05, the difference was statistically significant. Conclusion: The fusion protein containing single chain antibody was successfully prepared, which had good binding ability to A549 cells and inhibited the proliferation of tumor cells in vitro and in vivo, and provided the laboratory basis for the development of targeted anti-tumor drugs.

Preliminary study on application of programmed cell death 1 ligand 2 to the diagnosis of colorectal cancer in confocal laser endomicroscopy / 上海交通大学学报（医学版）

Objective:To investigate the relationship between expression of programmed cell death 1 ligand 2 (PD-L2) in colorectal cancer and prognosis, and explore the feasibility of application of PD-L2 in confocal laser endomicroscopy in the diagnosis of colorectal cancer. Methods:Immunohistochemistry was used to detect the expression of PD-L2 in 100 patients with colorectal cancer. The relationship between the expression levels and the prognosis of patients was analyzed. The expressions of PD-L2 in 30 cases of early colorectal cancer and adjacent normal mucosa were detected by immunohistochemistry and Western blotting. Confocal laser endomicroscopy was used to observe the difference in fluorescence intensity between early colorectal cancer and adjacent normal mucosa after being incubated with PD-L2 fluorescent antibody. Results:There were statistically significant differences in T-stage and distant metastasis between the patients with low and high expression of PD-L2, and they were both positively correlated with expression of PD-L2 (r=0.274, P=0.009; r=0.216, P=0.039). There was also a positive correlation between PD-L2 membrane expression and T stage (r=0.201, P=0.037). Survival analysis showed that the survival rate of patients with high PD-L2 expression was significantly lower than that of patients with low PD-L2 expression (P=0.000). The protein expression of PD-L2 in early colorectal cancer was significantly higher than that in adjacent normal mucosa. Under confocal laser endomicroscopy, the fluorescence intensity of early colorectal cancer was higher than that of adjacent normal mucosa. Conclusion:High expression of PD-L2 in colorectal cancer predicts poor prognosis in patients. Application of PD-L2 in confocal laser endomicroscopy may contribute to the diagnosis of colorectal cancer.

The mechanism and research progress of drug resistance of PD-1/PD-L1 immunotherapy in tumors / 药学学报

Programmed cell death protein 1 (PD-1) is an important immunosuppressive molecule, which combines with programmed cell death 1 ligand 1 (PD-L1) to initiate programmed T-cell death, leading to immune escape of tumor cells. Immune checkpoint inhibitors kill tumor cells by blocking the binding of PD-1 to PD-L1 and reactivating the patient's own immune system. With the approval of anti-PD-1 monoclonal antibodies nivolumab, pembrolizumab and anti-PD-L1 monoclonal antibody atezolizumab by FDA for the treatment of melanoma, advanced non-small cell lung cancer and other cancers, cancer treatment has ushered in a new dawn. However, only 20% of patients achieved long-term efficacy after treatment, and most patients relapsed later. Therefore, it is significant to identify effective biomarkers and develop new targets to improve the response of patients to immunotherapy. This article reviews on the mechanism of action of anti-PD-1/PD-L1 drugs in tumors, potential biomarkers and the mechanism of acquired drug resistance, as well as combination therapy under research.

Advances in hyperprogressive disease of PD-1/PD-L1 antibody drugs and rational drug therapy / 药学学报

With the significant breakthrough that programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) antibody drugs achieved promising clinical outcomes across various tumor types, immunotherapy targeting immune checkpoint has been considered a promising way to treat cancer. However, most recently studies suggest that the hyperprogressive disease occurred frequently during the therapy of using PD-1/PD-L1 antibody drugs and has become an urgent problem to be solved. In this review, we summarize the progress and potential reasons of hyperprogressive disease caused by PD-1/PD-L1 blockade, and further discuss its application based on the rational use of biomarkers for searching the benefit patients.

Immunostimulatory monoclonal antibodies for hepatocellular carcinoma therapy: Trends and perspectives

Hepatocellular carcinoma (HCC) is the second cause of cancer-related death in the world and is the main cause of death in cirrhotic patients. Unfortunately, the incidence of HCC has grown significantly in the last decade. Curative treatments such as surgery, liver transplantation or percutaneous ablation can only be applied in less than 30% of cases. The multikinase inhibitor sorafenib is the first line therapy for advanced HCC. Regorafenib is the standard of care for second-line patients. However, novel and more specific potent therapeutic approaches for advanced HCC are still needed. The liver constitutes a unique immunological microenvironment, although anti-tumor immunity seems to be feasible with the use of checkpoint inhibitors such as nivolumab. Efficacy may be further increased by combining checkpoint inhibitors or by applying loco-regional treatments. The success of immune checkpoint blockade has renewed interest in immunotherapy in HCC.

El hepatocarcinoma (HCC) es la segunda causa de muerte relacionada con el cáncer en el mundo y es la principal causa de muerte en pacientes cirróticos. Desafortunadamente, la incidencia de HCC ha crecido significativamente en la última década. Los tratamientos curativos como la cirugía, el trasplante de hígado o la ablación solo pueden aplicarse en menos del 30% de los casos. El sorafenib es el tratamiento de primera línea para el HCC avanzado, mientras que el regorafenib se reserva como segunda línea. Sin embargo, todavía son necesarios nuevos enfoques terapéuticos potentes y más específicos para el HCC avanzado. El hígado constituye un microambiente inmunológico único, aunque la inmunidad antitumoral parece ser factible mediante el uso de inhibidores de punto de control como nivolumab. La eficacia puede aumentarse adicionalmente combinando inhibidores de puntos de control inmunitario o aplicando tratamientos loco-regionales. En este sentido, el éxito del uso de anticuerpos monoclonales, que bloquean el control inmunitario, ha renovado el interés en la inmunoterapia para el HCC.

Expression of programmed cell death 1 receptor and its downstream cytokines in peripheral blood mononuclear cells of patients with generalized pustular psoriasis / 中华皮肤科杂志

Objective To determine the expression of programmed cell death 1 receptor (PDCD 1),its ligands and downstream nuclear factor kappa B (NF-κB) in peripheral blood mononuclear cells (PBMC) of patients with generalized pustular psoriasis (GPP).Methods The total RNA was extracted from 9 GPP patients and 10 healthy controls separately by using Trizol,and reverse transcription PCR (RT-PCR) was performed to determine the mRNA expression of PDCD1,programmed cell death 1 ligand 1 (PD-L1),PD-L2 and NF-κB.Enzyme-linked immunosorbent assay (ELISA) was conducted to the serum levels of interleukin-27 (IL-27),IL-22 and IL-4 in the peripheral blood of 23 GPP patients and 24 healthy controls.Results The mRNA expression of PDCD1 was significantly lower in the GPP group (3.13 ± 4.62) than in the healthy control group (23.70 ± 15.33,t =3.40,P ＜ 0.05).However,the mRNA expression of PD-L1 and PD-L2 was significantly higher in the GPP group than in the healthy control group (PD-LI:[5.70 ± 3.07] × 104 vs.[2.00 ± 1.98] × 104,t =2.96,P ＜ 0.05;PD-L2:[0.95 ± 0.71] × 10-4 vs.[0.16 ± 0.20] × 10-4,t =3.38,P ＜ 0.05).There was no significant difference in the mRNA expression of NF-κB between the GPP group and the healthy control group (P ＞ 0.05).The GPP group also showed significantly higher levels of IL-27,IL-22 and IL-4 compared with the healthy control group (all P ＜ 0.001).Conclusion PDCD1 and its ligands were abnormally expressed in the PBMC of patients with GPP,and may play an important role in the occurrence and development of GPP.

Immunotherapy for hepatocellular carcinoma: Research advances and clinical prospects / 第二军医大学学报

Hepatocellular carcinoma (HCC) is one of the most frequently diagnosed malignancies and the third leading cause of cancer-related deaths in the world. China is known as "the country with the highest prevalence of liver cancer", and more than half of the cases of HCC worldwide occur in China. Recently, immunotherapy for HCC has drawn wide attention owing to its satisfying effects on specific solid malignancies. Both basic and clinical researches on immunotherapy for HCC have made some progress, which has laid a foundation for future clinical application of immunotherapy in HCC patients. The main immunological strategies for HCC include adoptive immunotherapy, indirect immunotherapy, and indirect non-immunological therapy. Despite the potential benefits for HCC, challenges and obstacles of immunotherapy remain, such as the self-tolerance immune mechanism of the liver and the lack of ideal target antigen. In a word, the application of immunotherapy for HCC in clinical practice is a tough task to accomplish and a long way to go.

Overexpression of PD-L1 and PD-L2 Is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies. Recently, the overexpression of programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) has been shown to correlate with poor prognosis in many cancers. However, the expression of PD-L1 or PD-1 ligand 2 (PD-L2) and clinical outcomes have not been fully investigated in HCC. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded samples were obtained from 85 patients with HCC who underwent surgery. The expression of PD-Ls (PD-L1, PD-L2) was evaluated by immunohistochemical analysis. RESULTS: The proportion of high expression groups of PD-L1 and PD-L2 was 27.1% and 23.5%, respectively. Univariate analysis revealed that tumor size (p < 0.001), histological differentiation (p=0.010), PD-L1 expression (p < 0.001), and PD-L2 expression (p=0.039) were significant prognostic factors of overall survival in patients with HCC. Multivariate analysis revealed that overall tumor size (hazard ratio [HR], 4.131; 95% confidence interval [CI], 2.233 to 7.643; p < 0.001 and HR, 3.455; 95% CI, 1.967 to 6.067; p < 0.001) and PD-L1 expression (HR, 5.172; 95% CI, 2.661 to 10.054; p < 0.001 and HR, 3.730; 95% CI, 1.453 to 9.574; p=0.006) were independent prognostic values for overall and disease-free survival. Patients with high expression of PD-Ls had a significantly poorer survival than those with low expression (p < 0.001, p=0.034). CONCLUSION: The overexpression of PD-Ls in HCC patients is correlated with survival and tumor recurrence. Further evaluation of PD-1 and PD-Ls as therapeutic targets and predictive biomarkers for HCC is warranted.

PD1/PD-L1 Blockade therapy for cancer:influencing factors,predictive biomarkers and combined treatments / 国际药学研究杂志

Recently,programmed cell death 1/programmed cell death 1 ligand(PD-1/PD-L1)blockade has elicited clinical re-sponses and long-term remissions in a subset of patients with a broad spectrum of cancers. Unfortunately,a substantial number of pa-tients failed to respond to PD1/PD-L1 blockade. In this paper,we summarize our current understanding of the key factors accounting for the difference on treatment,and evaluate the dependability of several potential predictive biomarkers guiding PD1/PD-L1 blockade in cancer therapy. We also discuss a variety of combined treatments based on PD1/PD-L1 blockade.

Immunotherapy for hepatocellular carcinoma: research advances and clinical prospects / 第二军医大学学报

Hepatocellular carcinoma (HCC) is one of the most frequently diagnosed malignancies and the third leading cause of cancer-related deaths in the world.China is known as the country with the highest prevalence of liver cancer,and more than half of the cases of HCC worldwide occur in China.Recently,immunotherapy for HCC has drawn wide attention owing to its satisfying effects on specific solid malignancies.Both basic and clinical researches on immunotherapy for HCC have made some progress,which has laid a foundation for future clinical application of immunotherapy in HCC patients.The main immunological strategies for HCC include adoptive immunotherapy,indirect immunotherapy,and indirect non-immunological therapy.Despite the potential benefits for HCC,challenges and obstacles of immunotherapy remain,such as the self-tolerance immune mechanism of the liver and the lack of ideal target antigen.In a word,the application of immunotherapy for HCC in clinical practice is a tough task to accomplish and a long way to go.