Hamada Y., Tanoue K., Kita Y., Tanabe K., Hokonohara K., Wada M., Hozaka Y., Oi H., Nakayama C., Higashi M., Arigami T., Mori S., Ohtsuka T. . Vascular endothelial growth factor inhibitors pro2023 · 記述言語： 日本語 出版者・発行元： Scandinavian Journal of Gastroenterology Purpose: This study aims to investigate changes in the tumor immune environment of patients who underwent therapy with a vascular endothelial growth factor (VEGF) inhibitor for advanced colorectal cancer. Methods: Patients (n = 135) with T3 or T4 colorectal cancer were included in this retrospective study. They were classified as follows: patients who had not received preoperative treatment (UPFRONT group, n = 54), who had received FOLFOX as preoperative chemotherapy (FOLFOX group, n = 55), and who had undergone resection after combination FOLFOX and bevacizumab as unresectable colorectal cancer (B-MAB group, n = 26). The number of cytotoxic T lymphocytes (CTLs), FOXP3<sup>+</sup> lymphocytes (including regulatory T cells (Tregs)), CD163<sup>+</sup> monocytes (including M2-type tumor-associated macrophages (TAM-M2 type)), and programmed cell death 1 (PD-1)<sup>+</sup> lymphocytes was evaluated immunohistochemically in the cancer cell area (CC) and stromal cell area (ST) of surgical specimens, and compared among the three groups. Results: The CTL population did not differ among the three groups in both areas. In the B-MAB group, the numbers of PD-1<sup>+</sup> cells in the ST, FOXP3<sup>+</sup> lymphocytes in both areas, and CD163<sup>+</sup>monocytes in the ST was lower than that in the other two groups, and a correlation with the histological therapeutic effect was observed. Conclusions: In advanced colorectal cancer, VEGF inhibitors may decrease the number of PD-1<sup>+</sup> cells and inhibit the infiltration of FOXP3<sup>+</sup> lymphocytes and CD163<sup>+</sup>monocytes into the tumor environment. DOI： 10.1080/00365521.2023.2194011 Scopus PubMed
Hamada Y., Tanoue K., Arigami T., Yamakuchi M., Okawa M., Matsushita D., Takenouchi K., Yamada S., Maywar D.N., Nakayama C., Oyama Y., Higashi S., Fujisaki C., Hozaka Y., Kita Y., Hashiguchi T., Ohtsu1951 · 記述言語： 日本語 出版者・発行元： Cancers Background/Objectives: The response rate to immune checkpoint inhibitor (ICI) therapy is limited. Further, there is a need to discover biomarkers to predict therapeutic efficacy. The vascular endothelial growth factor (VEGF) is strongly associated with intra-tumoral immunity; however, its utility as a marker remains unknown. Therefore, our objectives were to examine the isoforms of VEGF and determine whether VEGF levels predict ICI efficacy. Methods: Levels of VEGF isoforms VEGF-A121 and VEGF-A165 were measured in stored serum samples obtained from 30 patients with advanced or recurrent gastric cancer who received nivolumab monotherapy at Kagoshima University Hospital, and the association with prognosis and treatment efficacy was retrospectively analyzed. Results: The serum levels of the total VEGF, VEGF-A121, and VEGF-A165 were not significantly associated with prognosis. However, the ratio of VEGF-A121/VEGF-A165 (VEGF-A121/165) exhibited a statistically significant (p = 0.0088) difference in progression-free survival (PFS) with the low-ratio group having a 67-day prolonged median PFS time. Under univariable analysis, only VEGF-A121/165 values exhibited reduced progression-free survival with statistical significance. When comparing treatment responses in the low (n = 15) and high (n = 15) serum VEGF-A-121/165 groups, RECIST evaluation was 3 to 0 for complete response (CR), 2 to 0 for partial response (PR), 3 to 2 for stable disease (SD), and 3 to 10 for progressive disease (PD). Patients with clinically unsettled PR or SD were classified as non-CR/non-PD (4 vs. 3), with a disease control rate of 80% vs. 33%. Conclusions: The serum VEGF-A121/165 ratio may represent a new, easily measured biomarker for predicting the therapeutic response to ICIs. DOI： 10.3390/cancers16233958 Scopus PubMed
Matsumoto R., Tanoue K., Nakayama C., Okawa M., Hozaka Y., Idichi T., Mataki Y., Ohtsuka T. . Strategies to Target the Tumor-Associated Macrophages in the Immunosuppressive Microenvironment of記述言語： 日本語 出版者・発行元： Cancers Pancreatic ductal adenocarcinoma (PDAC) is a critical disease requiring the development of novel effective therapeutic approaches due to its increasing global incidence and associated low survival rates. While immunotherapy, including immune checkpoint inhibitors, has shown efficacy against various tumors, developing an effective treatment approach for PDAC poses a challenge. This is primarily attributed to the complex and distinctive immune evasion mechanisms of PDAC. Recent studies have revealed that tumor-associated macrophages (TAMs) play a crucial role in enhancing immune evasion in PDAC. This role is mediated through multiple pathways, including cytokine secretion and the activation or suppression of diverse immune cells. A clear understanding of how macrophages contribute to PDAC proliferation could lead to the development of novel immune therapy approaches targeting TAMs. In this review, we summarized the multifaceted activities and roles of TAMs in PDAC and explored the potential effect of immunotherapeutic approaches on PDAC, with a particular focus on chimeric antigen receptor (CAR) macrophages. This review was based on promising findings from recent studies on CAR macrophage-based immunotherapy for solid tumors. DOI： 10.3390/cancers17183090 Scopus PubMed
Nakayama C., Tanoue K., Idichi T., Shimomura H., Kita Y., Hozaka Y., Shinden Y., Matsushita D., Nakajo A., Arigami T., Mataki Y., Kurahara H., Ohtsuka T. . Implications of PD-1, Tim-3, and TIG記述言語： 日本語 出版者・発行元： Anticancer research BACKGROUND/AIM: The development and application of cancer immunotherapy to pancreatic cancer has not progressed because its efficacy has not been proven in clinical trials. In this study, we aimed to explore potential targets of immune checkpoint inhibitor therapy for pancreatic cancer treatment. MATERIALS AND METHODS: We collected resected specimens from 40 patients with pancreatic cancer who underwent resection at our Institution without any preoperative treatment. We evaluated the expression of molecules in the programmed death receptor-1 (PD-1), T cell immunoglobulin mucin-3 (Tim-3)/Galectin-9, and CD155/T cell immunoreceptor with Ig and ITIM domains (TIGIT) pathways using immunohistochemical staining. The correlation between the expression pattern of these molecules and patient prognosis were assessed using Kaplan-Meier analysis. RESULTS: An increased number of CD8+ T cells in pancreatic cancer tissue was significantly associated with a better patient prognosis. Additionally, patients with a higher ratio of PD-1 expression to CD8+ T cells had a worse prognosis. We observed no correlation between the Tim-3/Galectin-9 and CD155/TIGIT pathways and patient prognosis. CONCLUSION: Modifications in the immune environment to increase T cell infiltration into tumors could result in the PD-1 pathway becoming a potential target to treat pancreatic cancer using immune checkpoint inhibition. DOI： 10.21873/anticanres.15824 Scopus PubMed
