Intratumoral heterogeneity impacts the response to anti-neu antibody therapy.

Background: Along with de novo resistance, continued exposure to trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2/neu) antibody, can lead to acquired resistance. In this study, we characterize a new anti-HER2/neu antibody resistant and metastatic mouse breast carcinoma cell line, TUBO-P2J. This cell line was developed during in vivo experiments using the antibody sensitive and non-metastatic tumor line TUBO.

Recipient NK cell inactivation and intestinal barrier loss are required for MHC-matched graft-versus-host disease.

Previous studies have shown a correlation between pretransplant conditioning intensity, intestinal barrier loss, and graft-versus-host disease (GVHD) severity. However, because irradiation and other forms of pretransplant conditioning have pleiotropic effects, the precise role of intestinal barrier loss in GVHD pathogenesis remains unclear. We developed GVHD models that allowed us to isolate the specific contributions of distinct pretransplant variables.

Anti-HER2/Neu passive-aggressive immunotherapy.

Preclinical studies have established that CD8 T cells are necessary for efficient immunotherapeutic regimens targeting avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2, best known as HER2/Neu). Recently, we extended upon these findings by demonstrating that anti-HER2/Neu therapy also requires CD4 T cells and CD40/CD40L signaling within the tumor microenvironment. Our results add to mounting evidence demonstrating that adaptive immunity is crucial to the efficacy of conventional and targeted anticancer chemotherapeutics.

Adaptive Immune Responses and HER2/neu Positive Breast Cancer.

Oncogenic signaling, such as HER2/neu signaling, has been shown to play major role for tumorigenesis in a subset of breast cancer patients. The use of anti-HER2/neu antibody has not only revealed the mechanisms for HER2/neu signaling but also shown a therapeutic advantage of its blockade. Indeed, the use of trastuzumab has greatly improved the treatment of HER2-positive breast cancer.

Effective anti-neu-initiated antitumor responses require the complex role of CD4+ T cells.

Purpose: Targeting oncogenic receptors with antibodies has been thought to suppress tumor growth mainly by interrupting oncogenic signals. Recently, the essential role for adaptive immunity, and CD8(+) T cells in particular, has been established as a major factor for anti-HER2/neu-mediated tumor regression. However, the role of CD4(+) T cells is still being defined.

Cetuximab-mediated tumor regression depends on innate and adaptive immune responses.

Epidermal growth factor receptor (EGFR) over-signaling leads to more aggressive tumor growth. The antitumor effect of Cetuximab, an anti-EGFR antibody, depends on oncogenic-signal blockade leading to tumor cell apoptosis and antibody dependent cell-mediated cytotoxicity (ADCC). However, whether adaptive immunity plays a role in Cetuximab-mediated tumor inhibition is unclear, as current xenograft models lack adaptive immunity and human-EGFR-dependent mouse tumor cell lines are unavailable.

Targeting and utilizing primary tumors as live vaccines: changing strategies.

Tumor metastases and relapse are the major causes of morbidity and mortality in cancer. Although surgery, chemotherapy and/or radiation therapy can typically control primary tumor growth, metastatic and relapsing tumors are often inaccessible or resistant to these treatments. An adaptive immune response can be generated during these conventional treatments of the primary tumor, and presumably both the primary tumor and secondary metastases share many of the same or similar antigenic characteristics recognized by the immune system.

The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity.

Anti-HER2/neu antibody therapy is reported to mediate tumor regression by interrupting oncogenic signals and/or inducing FcR-mediated cytotoxicity. Here, we demonstrate that the mechanisms of tumor regression by this therapy also require the adaptive immune response. Activation of innate immunity and T cells, initiated by antibody treatment, was necessary.