Kazunoshin Tachibana

Myeloid-derived suppressor cells are increased and correlated with type 2 immune responses, malnutrition, inflammation, and poor prognosis in patients with breast cancer

Myeloid-derived suppressor cells (MDSCs) have been identified in the majority of patients and experimental mice with tumors by their suppression of T cell activation. MDSCs have also been reported to be associated with chronic inflammation. In advanced cancer, the T helper (Th) cell balance tends to shift from Th1 to Th2 predominance, and immune function, including cell-mediated immunity, is impaired by cytokines produced by Th2 cells. The present study examined the correlations between MDSC levels and inflammation, immune suppression, malnutrition, and poor prognosis in 155 patients with breast cancer. The levels of MDSCs in preoperative patients and in patients with recurrent breast cancer were significantly higher compared with postoperative patients, patients with recurrent breast cancer who received chemotherapy and healthy volunteers. The MDSC levels of preoperative patients were significantly positively correlated with interleukin (IL)-6 production by peripheral blood mononuclear cells (PBMCs), the neutrophil/lymphocyte ratio and C-reactive protein, and were negatively correlated with the production of interferon-γ and IL-12, serum concentration of rapid turnover protein, and the stimulation index. These patients were divided into two groups based on the levels of MDSCs. In preoperative patients with MDSC levels >1.0% of total PBMCs, the overall survival of patients with stage IV disease was significantly shorter compared with other disease stages, and was also significantly shorter compared with patients with MDSC levels <1.0% of total PBMCs. Thus, the MDSC levels of preoperative patients may function as a good prognostic indicator, particularly in patients with advanced breast cancer.

Abscopal effect following radiation monotherapy in breast cancer: A case report

Radiotherapy has been found to be valuable for the control and eradication of local foci in various malignant tumors. The abscopal effect is determined as a systemic antitumor response at a distance from the irradiation site invoked by local irradiation. We herein present an extremely rare case of breast cancer in a 64-year-old woman, in whom the abscopal effect was observed after radiotherapy induced an antitumor response in all metastatic lesions, without any combination therapy. The patient was admitted to our hospital complaining of a breast mass and pain at the left hip, and was diagnosed with breast cancer with multiple bone, lung and lymph node metastases. She received treatment with local radiotherapy delivered to the breast tumor and some of the bone metastases but did not receive chemotherapy due to her poor performance status. However, 10 months after radiotherapy, spontaneous regression was observed, not only within the irradiated field, but also in the non-irradiated areas. All signs of cancer throughout the body disappeared, and the patients performance status drastically improved. To the best of our knowledge, there have been no reports of advanced breast cancer cases in which the abscopal effect was observed after radiation monotherapy; therefore, this case report is extremely rare and highly valuable.

Glycosyltransferase Gene Expression Identifies a Poor Prognostic Colorectal Cancer Subtype Associated with Mismatch Repair Deficiency and Incomplete Glycan Synthesis

Purpose: We aimed to discover glycosyltransferase gene (glycogene)-derived molecular subtypes of colorectal cancer associated with patient outcomes. Experimental Design: Transcriptomic and epigenomic datasets of nontumor, precancerous, cancerous tissues, and cell lines with somatic mutations, mismatch repair status, clinicopathologic and survival information were assembled (n = 4,223) and glycogene profiles were analyzed. IHC for a glycogene, GALNT6, was conducted in adenoma and carcinoma specimens (n = 403). The functional role and cell surface glycan profiles were further investigated by in vitro loss-of-function assays and lectin microarray analysis. Results: We initially developed and validated a 15-glycogene signature that can identify a poor-prognostic subtype, which closely related to deficient mismatch repair (dMMR) and GALNT6 downregulation. The association of decreased GALNT6 with dMMR was confirmed in multiple datasets of tumors and cell lines, and was further recapitulated by IHC, where approximately 15% tumors exhibited loss of GALNT6 protein. GALNT6 mRNA and protein was expressed in premalignant/preinvasive lesions but was subsequently downregulated in a subset of carcinomas, possibly through epigenetic silencing. Decreased GALNT6 was independently associated with poor prognosis in the IHC cohort and an additional microarray meta-cohort, by multivariate analyses, and its discriminative power of survival was particularly remarkable in stage III patients. GALNT6 silencing in SW480 cells promoted invasion, migration, chemoresistance, and increased cell surface expression of a cancer-associated truncated O-glycan, Tn-antigen. Conclusions: The 15-glycogene signature and the expression levels of GALNT6 mRNA and protein each serve as a novel prognostic biomarker, highlighting the role of dysregulated glycogenes in cancer-associated glycan synthesis and poor prognosis. Clin Cancer Res; 24(18); 4468–81. ©2018 AACR.

TBX19 is overexpressed in colorectal cancer and associated with lymph node metastasis

The T-box 19 (TBX19) gene encodes a transcription factor characterized by a highly conserved DNA-binding motif (T-box). Recent studies have revealed that TBX19 has been identified as one of the genes activated by KRAS mutations, and is upregulated in colon adenoma. These results indicate that TBX19 may work as an oncogene in colorectal cancer (CRC). However, the expression and role of TBX19 have yet to be investigated. Here, we investigated TBX19 mRNA and protein expressions in colon cancer cells or surgically resected CRC. We found that TBX19 mRNA expression was significantly increased in tumorous tissues compared to that in non-tumorous tissues, and increased TBX19 mRNA expression was associated with positive lymph node metastasis in our cohort. The expression of TBX19 mRNA was not correlated with that of TBX19 protein in tissue sample taken from the CRC patients. Moreover, TBX19 showed positive staining even in the normal colonic tissues and the adjacent non-tumorous tissues. These results suggest that the expression of TBX19 protein is not correlated with the expression of TBX19 mRNA. In addition, our results promote further investigations into the impact of TBX19 upregulation on colorectal carcinogenesis, as well as the underlying mechanisms.

IL-17 and VEGF are increased and correlated to systemic inflammation, immune suppression, and malnutrition in patients with breast cancer:

Relationships between inflammation and innate immunity in cancer are widely accepted today; however, the precise cell mechanisms mediating these relationships have not yet been elucidated. Interleukin (IL)-17 is a proinflammatory cytokine that has been reported to induce inflammation in patients with autoimmune diseases. Myeloid-derived suppressor cells (MDSC) may contribute to the negative regulation of immune responses during cancer and inflammation. Vascular endothelial growth factor (VEGF) is reported to have multiple biological actions including increasing vascular permeability, neovascularization, and possible inhibition of immune function in malignant diseases. This study investigated the status of systemic inflammation and immune suppression associated with IL-17 and VEGF in patients with breast cancer. IL-17 production and the serum levels of VEGF were also increased in advanced stages of the disease. The production of IL-12, which induces Th1 cells, and the stimulation index (SI), which is a marker of cell-mediated immune function, were both shown to decrease along with disease advancement. Also, the production of IL-17 and the VEGF levels were both positively correlated with the levels of MDSC, the neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP), and were inversely correlated with IL-12 production and the SI. Nutritional markers, including prealbumin (PA), transferrin (TF), and retinol-binding protein (RBP), were also shown to be significantly lower in patients with high production of IL-17 or high levels of VEGF. These data clearly showed that IL-17 and VEGF, whose levels correlated with each other and with those of MDSC, were significantly associated with disease advancement, systemic inflammation, suppression of cell-mediated immunity including Th1 induction, and malnutrition.