• Journal of Korean Neurosurgical Society
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• v.64 no.1
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• pp.100-109
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• 2021

Objective : Diffuse astrocytic tumour (DAT) is a diffuse infiltrative astrocytoma tumour accompanied by molecular parameters such as the presence or absence of isocitrate dehydrogenase (IDH) gene mutations. Ki-67 is a marker for DAT proliferation, while programmed death ligand 1 (PD-L1) indicates an immune evasion mechanism. This study aimed to analyze the correlation among mutant IDH1 R132H, Ki-67, and PD-L1 immunoexpression in the DAT. Methods : A cross-sectional study was carried out on 30 paraffin blocks of DAT cases. Paraffin block samples consist of grade II (n=14), grade III (n=8), and grade IV (n=8). In this study, the immunohistochemistry-staining of mutant IDH1 R132H, Ki-67, and PD-L1 were carried out to determine the frequency of DAT with IDH1 mutations. Results : Our study shown the frequency of IDH1 mutations in grade II 50.0% (7/14), grade III 37.5% (3/8), and grade IV 12.5% (1/8). Our study also showed a difference in Ki-67 and PD-L1 expression between each the degree of DAT histopathology (p=0.0001 and p=0.002, respectively). There was an association between both mutant IDH1 R132H, and Ki-67 with PD-L1 expression in DAT (p=0.0087 and p=0.0049, respectively). Conclusion : DAT with the mutant IDH1 is frequently observed in grade II and small number of grade III. The expression of wild type IDH1, Ki-67, and PD-L1 were found to be higher in high grade DAT (grade III and grade IV). There is a correlation between each of mutant IDH1 status and Ki-67 with PD-L1 expression in DAT.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.41
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• pp.56.1-56.6
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• 2019

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.

• IMMUNE NETWORK
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• v.20 no.1
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• pp.8.1-8.15
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• 2020

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 anticancer 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.

• Journal of Gastric Cancer
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• v.16 no.1
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• pp.1-7
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• 2016

Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is one of the four subtypes of gastric carcinoma (GC), as defined by the novel classification recently proposed by The Cancer Genome Atlas. EBVaGC has several clinicopathological features such as longer survival and higher frequency of lymphoepithelioma-like carcinoma (LELC) and carcinoma with Crohn's disease-like lymphoid reaction that distinguish it from EBV-negative GC. The intensity and pattern of host cellular immune response in GC have been found to significantly correlate with the prognosis of patients with GC, suggesting that immune reaction and tumor microenvironment have critical roles in the progression of GC, and in particular, EBVaGC. Here, we reviewed the cellular and molecular mechanisms underlying prominent immune reactions in patients with EBVaGC. In EBVaGC, deregulation of the expression of immune response-related genes promotes marked intra-or peritumoral immune cell infiltration. The expression of programmed death receptor-ligand 1 is known to be increased in EBVaGC, and therefore, it has been proposed as a favorable prognostic factor for patients with EBVaGC, albeit some data supporting this claim are controversial. Overall, the underlying mechanisms and clinical significance of the host cellular immune response in patients with EBVaGC have not been thoroughly elucidated. Therefore, further research is necessary to better understand the role of tumor microenvironment in EBVaGC.

• Journal of Gastric Cancer
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• v.18 no.1
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• pp.1-19
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• 2018

Gastric cancer (GC) is the second leading cause of cancer mortality and the fourth most commonly diagnosed malignant diseases. While continued efforts have been focused on GC treatment, the introduction of trastuzumab marked the beginning of a new era of target-specific treatments. Considering the diversity of mutations in GC, satisfactory results obtained from various target-specific therapies were expected, yet most of them were unsuccessful in controlled clinical trials. There are several possible reasons underlying the failures, including the absence of patient selection depending on validated predictive biomarkers, the inappropriate combination of drugs, and tumor heterogeneity. In contrast to targeted agents, immuno-oncologic agents are designed to regulate and boost immunity, are not target-specific, and may overcome tumor heterogeneity. With the successful establishment of predictive biomarkers, including Epstein-Barr virus pattern, microsatellite instability status, and programmed death-ligand 1 (PD-L1) expression, as well as ideal combination regimens, a new frontier in the immuno-oncology of GC treatment is on the horizon. Since the field of immuno-oncology has witnessed innovative, practice-changing successes in other cancer types, several trials on GC are ongoing. Among immuno-oncologic therapies, immune checkpoint inhibitors are the mainstay of clinical trials performed on GC. In this article, we review target-specific agents currently used in clinics or are undergoing clinical trials, and highlight the future clinical application of immuno-oncologic agents in inoperable GC.

• Molecules and Cells
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• v.46 no.3
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• pp.142-152
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• 2023

Nuclear factor erythroid 2-related factor 2 (Nrf2) mediates the cellular antioxidant response, allowing adaptation and survival under conditions of oxidative, electrophilic and inflammatory stress, and has a role in metabolism, inflammation and immunity. Activation of Nrf2 provides broad and long-lasting cytoprotection, and is often hijacked by cancer cells, allowing their survival under unfavorable conditions. Moreover, Nrf2 activation in established human tumors is associated with resistance to chemo-, radio-, and immunotherapies. In addition to cancer cells, Nrf2 activation can also occur in tumor-associated macrophages (TAMs) and facilitate an anti-inflammatory, immunosuppressive tumor immune microenvironment (TIME). Several cancer cell-derived metabolites, such as itaconate, L-kynurenine, lactic acid and hyaluronic acid, play an important role in modulating the TIME and tumor-TAMs crosstalk, and have been shown to activate Nrf2. The effects of Nrf2 in TIME are context-depended, and involve multiple mechanisms, including suppression of proinflammatory cytokines, increased expression of programmed cell death ligand 1 (PD-L1), macrophage colony-stimulating factor (M-CSF) and kynureninase, accelerated catabolism of cytotoxic labile heme, and facilitating the metabolic adaptation of TAMs. This understanding presents both challenges and opportunities for strategic targeting of Nrf2 in cancer.

• Journal of Breast Cancer
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• v.21 no.4
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• pp.406-414
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• 2018

Purpose: T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) is an emerging immune response molecule related to T-cell anergy. There has been tremendous interest in breast cancer targeting immune checkpoint molecules, especially in the triple-negative breast cancer (TNBC). This study was designed to investigate TIM-3 expression on tumor infiltrating lymphocytes (TILs), its relationships with clinicopathological parameters and expression of programmed death receptor 1 (PD-1)/programmed death receptor ligand 1 (PD-L1), and its prognostic role. Methods: Immunohistochemistry on tissue microarray blocks produced from 109 samples of invasive ductal carcinoma type TNBC was performed with antibodies toward TIM-3, PD-1, PD-L1 and breast cancer-related molecular markers. Associations between their expression and clinicopathological parameters as well as survival analyses were performed. Results: TIM-3 was expressed in TILs from all 109 TNBCs, consisting of 17 cases (<5%), 31 cases (6%-25%), 48 cases (26%-50%), and 13 cases (>51%). High TIM-3 was significantly correlated with younger patients (p=0.0101), high TILs (p=0.0029), high tumor stage (p=0.0018), high PD-1 (p=0.0001) and high PD-L1 (p=0.0019), and tended to be associated with higher histologic grade, absence of extensive in situ components and microcalcification. High TIM-3 expression was significantly associated with a combinational immunophenotype group of high PD-L1 and high PD-1 (p<0.0001). High TIM-3 demonstrated a significantly better disease-free survival (DFS) (p<0.0001) and longer overall survival (OS) (p=0.0001), together with high TILs and high PD-1. In univariate survival analysis, high TIM-3 showed reduced relapse risk (p<0.0001) and longer OS (p=0.0003), together with high PD-1 expression. In multivariate analysis, high TIM-3 was statistically significant in predicting prognosis, showing better DFS (hazard ratio [HR], 0.0994; 95% confidence interval [CI], 0.0296-0.3337; p=0.0002) and longer OS (HR, 0.1109; 95% CI, 0.0314-0.3912; p=0.0006). Conclusion: In this study, we demonstrate that TIM-3 expression is an independent positive prognostic factor in TNBC, despite its association with poor clinical and pathologic features.

• Journal of Digestive Cancer Research
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• v.10 no.2
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• pp.65-73
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• 2022

A breakthrough in immunotherapy has changed the outlook for metastatic colorectal cancer (mCRC) treatment as the immune surveillance evasion mechanism of tumor cells has been continuously elucidated. Immune checkpoint inhibitors (ICI), such as pembrolizumab, nivolumab, and ipilimumab, which block immune checkpoint receptors or ligands have been approved for the treatment of mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) mCRC based on numerous clinical studies. However, 50% of dMMR/MSI-H mCRC and most mismatch repair proficient/microsatellite stable mCRC remained unresponsive to current immunotherapy. Clinical trials on combination therapy that adds various treatments, such as target agents, chemotherapy, or radiation therapy to ICI, have been actively conducted to overcome this immunotherapy limitation. Further studies on safety and efficacy are needed although several trials presented promising data. Additionally, dMMR/MSI-H, tumor mutation burden, and programmed cell death ligand-1 expression have been studied as biomarkers for predicting the treatment response to immunotherapy, but the discovery and validation of more sensitively predictable biomarkers remained necessary. Thus, this study aimed to review recent studies on immunotherapy in mCRC, summarize the efficacy and limitation of immunotherapy, and describe the biomarkers that predict treatment response.

• Journal of Gastric Cancer
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• v.23 no.3
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• pp.410-427
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• 2023

Recent advances in artificial intelligence (AI) have provided novel tools for rapid and precise pathologic diagnosis. The introduction of digital pathology has enabled the acquisition of scanned slide images that are essential for the application of AI. The application of AI for improved pathologic diagnosis includes the error-free detection of potentially negligible lesions, such as a minute focus of metastatic tumor cells in lymph nodes, the accurate diagnosis of potentially controversial histologic findings, such as very well-differentiated carcinomas mimicking normal epithelial tissues, and the pathological subtyping of the cancers. Additionally, the utilization of AI algorithms enables the precise decision of the score of immunohistochemical markers for targeted therapies, such as human epidermal growth factor receptor 2 and programmed death-ligand 1. Studies have revealed that AI assistance can reduce the discordance of interpretation between pathologists and more accurately predict clinical outcomes. Several approaches have been employed to develop novel biomarkers from histologic images using AI. Moreover, AI-assisted analysis of the cancer microenvironment showed that the distribution of tumor-infiltrating lymphocytes was related to the response to the immune checkpoint inhibitor therapy, emphasizing its value as a biomarker. As numerous studies have demonstrated the significance of AI-assisted interpretation and biomarker development, the AI-based approach will advance diagnostic pathology.

• Journal of Chest Surgery
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• v.56 no.2
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• pp.67-74
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• 2023

Perioperative treatment with conventional cytotoxic chemotherapy for resectable non-small cell lung cancer (NSCLC) has proven clinical benefits in terms of achieving a higher overall survival (OS) rate. With its success in the palliative treatment of NSCLC, immune checkpoint blockade (ICB) has now become an essential component of treatment, even as neoadjuvant or adjuvant therapy in patients with operable NSCLC. Both pre- and post-surgery ICB applications have proven clinical efficacy in preventing disease recurrence. In addition, neoadjuvant ICB combined with cytotoxic chemotherapy has shown a significantly higher rate of pathologic regression of viable tumors compared with cytotoxic chemotherapy alone. To confirm this, an early signal of OS benefit has been shown in a selected population, with programmed death ligand 1 expression ≥50%. Furthermore, applying ICB both pre- and post-surgery enhances its clinical benefits, as is currently under evaluation in ongoing phase III trials. Simultaneously, as the number of available perioperative treatment options increases, the variables to be considered for making treatment decisions become more complex. Thus, the role of a multidisciplinary team-based treatment approach has not been fully emphasized. This review presents up-to-date pivotal data that lead to practical changes in managing resectable NSCLC. From the medical oncologist's perspective, it is time to dance with surgeons to decide on the sequence of systemic treatment, particularly the ICB-based approach, accompanying surgery for operable NSCLC.