Pulmonary metastasis of breast cancer requires recruitment and expansion of T regulatory cells (Tregs) that promote escape from host protective immune cells. However, it remains unclear precisely how tumors recruit Tregs to support metastatic growth. Here we report the mechanistic involvement of a unique and previously undescribed subset of regulatory B cells. These cells, designated tumor-evoked Bregs (tBregs), phenotypically resemble activated but poorly proliferative mature B2 cells (CD19+ CD25High CD69High) that express constitutively active Stat3 and B7-H1High CD81High CD86High CD62LLowIgMInt. Our studies with the mouse 4T1 model of breast cancer indicate that the primary role of tBregs in lung metastases is to induce TGFβ-dependent conversion of FoxP3+ Tregs from resting CD4+ T cells. In the absence of tBregs, 4T1 tumors cannot metastasize into the lungs efficiently due to poor Treg conversion. Our findings have important clinical implications, since they suggest that tBregs must be controlled to interrupt the initiation of a key cancer-induced immunosuppressive event that is critical to support cancer metastasis.
We previously reported the beneficial effects of combination therapy of interferon (IFN)-a/5-fluorouracil (FU) for advanced hepatocellular carcinoma (HCC) with tumour thrombi in the major portal branches. This report describes the results of longer follow-up and includes more than double the number of patients relative to the original report, and evaluates the role of IFN-a/type 2 interferon receptor (IFNAR2) expression on the response to the combination therapy. The study subjects were 55 patients with advanced HCC and tumour thrombi in the major branches of the portal vein (Vp3 or 4). They were treated with at least two courses of IFN-a/5-FU without major complication. In the 55 patients, 24 (43.6%) showed objective response (eight (14.5%) showed complete response, 16 (29.1%) partial response), four (7.3%) showed no response, and 27 (49.1%) showed progressive disease. Immunohistochemically, IFNAR2 expression was detected in nine out of 13 (69.2%) patients. There was significant difference in the time-to-progression survival (P ¼ 0.0002) and the overall survival (Po0.0001) between IFNAR2-positive and -negative cases. There was a significant correlation between IFNAR2 expression and response to IFN-a/5-FU combination therapy in univariate analysis (P ¼ 0.0070). IFN-a/5-FU combination therapy is a promising modality for advanced HCC with tumour thrombi in the major portal branches and could significantly depend on IFNAR2 expression.
Recent
advances in high resolution mass spectrometry (MS) instrumentation
and semi-automated software have led to a push toward the use of MS-based
methods for quality control (QC) testing of therapeutic proteins in
a cGMP environment. The approach that is most commonly being proposed
for this purpose is known as the multi-attribute method (MAM). MAM
is a promising approach that provides some distinct benefits compared
to conventional methods currently used for QC testing of protein therapeutics,
such as CEX, HILIC, and CE-SDS. Because MS-based methods have not
been regularly used in this context in the past, new scientific and
regulatory questions should be addressed prior to the final stages
of implementation. We have categorized these questions into four major
aspects for MAM implementation in a cGMP environment for both new
and existing products: risk assessment, method validation, capabilities
and specificities of the New Peak Detection (NPD) feature, and comparisons
to conventional methods. This perspective outlines considerations
for each of these main points and suggests approaches to help address
potential issues.
Our study showed that the expression of VEGF and Ang-2 correlated with MVD. Strong Ang-2 expression and/or high nuclear expression of HIF-1alpha is a significant predictive factor for recurrence after curative resection in HCC patients.
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