Nucleic acid-triggered tumoral immunity propagates pH-selective therapeutic antibodies through tumor-driven epitope spreading.

Important roles of humoral tumor immunity are often pointed out; however, precise profiles of dominant antigens and developmental mechanisms remain elusive. We systematically investigated the humoral antigens of dominant intratumor immunoglobulin clones found in human cancers. We found that approximately half of the corresponding antigens were restricted to strongly and densely negatively charged polymers, resulting in simultaneous reactivities of the antibodies to both densely sulfated glycosaminoglycans (dsGAGs) and nucleic acids (NAs). These anti-dsGAG/NA antibodies matured and expanded via intratumoral immunological driving force of innate immunity via NAs. These human cancer-derived antibodies exhibited acidic pH-selective affinity across both antigens and showed specific reactivity to diverse spectrums of human tumor cells. The antibody-drug conjugate exerted therapeutic effects against multiple cancers in vivo by targeting cell surface dsGAG antigens. This study reveals that intratumoral immunological reactions propagate tumor-oriented immunoglobulin clones and demonstrates a new therapeutic modality for the universal treatment of human malignancies.

Optimal diagnostic method using multidetector-row computed tomography for predicting lymph node metastasis in colorectal cancer.

BACKGROUND: Prediction of nodal involvement in colorectal cancer is an important aspect of preoperative workup to determine the necessity of preoperative treatment and the adequate extent of lymphadenectomy during surgery. This study aimed to investigate newer multidetector-row computed tomography (MDCT) findings for better predicting lymph node (LN) metastasis in colorectal cancer. METHODS: Seventy patients were enrolled in this study; all underwent MDCT prior to surgery and upfront curative resection for colorectal cancer. LNs with a short-axis diameter (SAD) ≥ 4 mm were identified on MDCT images, and the following measures were recorded by two radiologists independently: two-dimensional (2D) SAD, 2D long-axis diameter (LAD), 2D ratio of SAD to LAD, 2D CT attenuation value, three-dimensional (3D) SAD, 3D LAD, 3D SAD to LAD ratio, 3D CT attenuation value, LN volume, and presence of extranodal neoplastic spread (ENS), as defined by indistinct nodal margin, irregular capsular enhancement, or infiltration into adjacent structures. RESULTS: Forty-six patients presented 173 LNs with a SAD ≥ 4 mm, while 24 patients exhibited pathologically confirmed LN metastases. Receiver operating characteristic analysis revealed that 2D LAD was the most sensitive measure for LN metastases with an area under the curve of 0.752 (cut-off value, 7.05 mm). When combined with CT findings indicating ENS, 2D LAD (> or ≤ 7 mm) showed enhanced predictive power for LN metastases (area under the curve, 0.846; p < 0.001). CONCLUSIONS: LAD in axial MDCT imaging is the most sensitive measure for predicting colorectal LN metastases, especially when MDCT findings of ENS are observed.

Aberrant Cadherin11 expression predicts distant metastasis of gastric cancer.

The prognosis of gastric cancer (GC) is significantly affected by distant metastases and postoperative recurrences. Bone metastasis is one of the worst prognostic metastases in GC; however, its molecular mechanisms and predictive biomarkers remain elusive. In prostate and breast cancers, it has been reported that overexpression of Cadherin 11 (CDH11), a mesenchymal cell-cell contact factor, is known to be correlated with bone metastasis. Overexpression of CDH11 mRNA in bulk GC tissues has also been reported to be associated with a worse prognosis. However, a more precise evaluation of CDH11 expression in GC cells is necessary to establish a robust link between CDH11 and metastatic features of GC. We performed immunohistochemical analysis of CDH11 expression in 342 GC cases, of which specimens were obtained at the time of surgery, with a special focus on its aberrant membranous expression in GC cells. The correlations between aberrant CDH11 expression and distant metastases and the prognosis of GC cases were statistically investigated. Approximately half of the GC cases investigated showed aberrant expression of CDH11 in the GC cells of primary lesions. Aberrant CDH11 expression was statistically associated with bone metastasis of GCs. Moreover, metastases to the liver and distant lymph nodes were also statistically correlated with CDH11 expression. Aberrant CDH11 expression in GC cells in primary tumor lesions was shown to be a predictive biomarker of distant metastases in GC. GCs with CDH11 expression require preventive clinical attention for the detection of metastatic lesions.