櫻井 浩平

The effectiveness of immune checkpoint inhibitors is diminished by the presence of myeloid-derived suppressor cells (MDSCs). Recent studies indicate that the NLR family pyrin domain-containing 3 (NLRP3) inflammasome regulates MDSC function, thereby reducing the efficacy of immune checkpoint inhibitors. However, the specific mechanism by which NLRP3 expression induces the immunosuppressive effects in MDSCs remains unclear. Here, we demonstrate that the adenosine triphosphate (ATP)-NLRP3 inflammasome axis enhances the immunosuppressive effects of MDSCs. We found that ATP increases the mRNA levels of immunosuppressive molecules in MDSCs, leading to the suppression of T cell proliferation. Additionally, we showed the efficacy of a novel immune checkpoint therapy that combines an ATP receptor inhibitor (P2X7 receptor inhibitor), an NLRP3 inhibitor, and an anti-PD-L1 antibody (Ab). This combination treatment significantly inhibited tumor growth compared to treatment with only the NLRP3 inhibitor and anti-PD-L1 Ab. These results suggest that the ATP-NLRP3 axis enhances the immunosuppressive effect of MDSCs. In conclusion, this study elucidates the mechanism through which MDSCs acquire immunosuppressive functions, potentially informing the development of novel cancer immunotherapies.

The Switch/Sucrose Nonfermentable (SWI/SNF) complexes are chromatin remodeling factors that consist of multiple protein subunits. Each subunit plays a distinct role in gene regulation and is aberrantly expressed in tumors, such as neuroendocrine neoplasms (NENs). BRG1-associated factor 53B (BAF53B), which is also known as ACTL6B, is a neuron-specific subunit that acts as a regulator during neurogenesis. Because the BAF53B expression pattern in tumors is unknown, the present study investigated the expression in cell lines and tissues. Publicly available transcriptome data indicated that BAF53B mRNA was highly expressed in NEN-derived cell lines. We performed immunohistochemical staining on tissue microarrays of different types of NENs with neuroendocrine (NE) marker expression (n = 117) (small cell lung carcinoma (SCLC)lung carcinoid (LC), gastroenteropancreatic-NEN (GEP-NEN), esophageal neuroendocrine carcinoma (ENEC), medullary thyroid carcinoma (MTC), neuroblastoma (NB), and pheochromocytoma (PHEO)) and non-NENs (n = 178). While few positive cells were observed in many cases of non-NENs (e.g., lung adenocarcinoma), positive expression was found in cases of NENs (SCLC (14/19, 73.7%), LC (12/16, 75.0%), GEP-NEN (4/9, 44.4%), ENEC (1/2, 50.0%), MTC (24/27, 88.9%), NB (18/20, 90.0%), and PHEO (16/24, 66.7%)). In NCI-H889 cells, BAF53B knockdown did not affect the cellular viability, and its effect on NE marker expression was only marginal. However, a gene expression microarray analysis suggested that BAF53B-regulated genes were associated with the development and progression of NENs. Our analysis revealed that BAF53B was an immunohistochemical marker for specific NENs, indicating its potentially important role in the pathogenesis.

Prospero homeobox protein 1 (PROX1) is aberrantly expressed in tumors, including neuroendocrine neoplasms (NENs); however, the detailed expression pattern remains elusive. This study aimed to immunohistochemically assess PROX1 expression. Immunohistochemistry (IHC) for PROX1 was performed on tissue microarrays of normal tissues (n = 107), NENs (n = 152) (small cell lung carcinoma [SCLC], lung carcinoid [LC], gastroenteropancreatic-NEN [GEP-NEN], esophageal neuroendocrine carcinoma [ENEC], medullary thyroid carcinoma [MTC], neuroblastoma [NB], and pheochromocytoma [PHEO]), and non-NENs (n = 469). In normal tissues, PROX1 was expressed in lymphatic endothelial cells and a subset of epithelial cells in the gastrointestinal tract and the distal convoluted tubules. In NENs, the positive expression was observed in the nucleus of tumor cells in 19/26 SCLC (73.1%), 13/16 LC (81.3%), 10/15 GEP-NEN (66.7%), 2/2 ENEC (100%), 17/43 MTC (39.5%), 1/25 NB (4.0%), and 0/25 PHEO (0%). Although PROX1 was negative in many non-NENs, our analysis revealed high expression in certain cases with medulloblastoma and one case with juvenile granulosa cell tumor. PROX1 was expressed in specific cases with epithelial NENs and some cases with non-NENs. Analysis of PROX1 should provide insights into the molecular characteristics of distinct tumors.

Preexisting cardiovascular disease (CVD) is a pivotal risk factor for severe coronavirus disease 2019 (COVID-19). We investigated the longitudinal (over 1 year and 9 months) humoral and cellular responses to primary series and booster doses of mRNA COVID-19 vaccines in patients with CVD. Twenty-six patients with CVD who received monovalent mRNA COVID-19 vaccines were enrolled in this study. Peripheral blood samples were serially drawn nine times from each patient. IgG against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) was measured using an enzyme-linked immunosorbent assay. The numbers of interferon-γ-releasing cells in response to SARS-CoV-2 peptides were measured using an enzyme-linked immunospot assay. The RBD-IgG titers increased 2 weeks after the primary series and booster vaccination and waned 6 months after vaccination. The S1-specific T cell responses in patients aged < 75 years were favorable before and after booster doses; however, the Omicron BA.1-specific T cell responses were poor. These results suggest that regular vaccination is useful to maintain long-term antibody levels and has implications for booster dose strategies in patients with CVD. Additional booster doses, including Omicron variant-adapted mRNA vaccines, may be recommended for patients with CVD, regardless of age.