Taxanes trigger cancer cell killing in vivo by inducing non-canonical T cell cytotoxicity.

Although treatment with taxanes does not always lead to clinical benefit, all patients are at risk of their detrimental side effects such as peripheral neuropathy. Understanding the in vivo mode of action of taxanes can help design improved treatment regimens. Here, we demonstrate that in vivo, taxanes directly trigger T cells to selectively kill cancer cells in a non-canonical, T cell receptor-independent manner. Mechanistically, taxanes induce T cells to release cytotoxic extracellular vesicles, which lead to apoptosis specifically in tumor cells while leaving healthy epithelial cells intact. We exploit these findings to develop an effective therapeutic approach, based on transfer of T cells pre-treated with taxanes ex vivo, thereby avoiding toxicity of systemic treatment. Our study reveals a different in vivo mode of action of one of the most commonly used chemotherapies, and opens avenues to harness T cell-dependent anti-tumor effects of taxanes while avoiding systemic toxicity.

Blood-circulating EV-miRNAs, serum TARC, and quantitative FDG-PET features in classical Hodgkin lymphoma.

Blood-based biomarkers are gaining interest for response evaluation in classical Hodgkin lymphoma (cHL). However, it is unknown how blood-based biomarkers relate to quantitative 18F-FDG-PET features. We correlated extracellular vesicle-associated miRNAs (EV-miRNA), serum TARC, and complete blood count (CBC) with PET features (e.g., metabolic tumor volume [MTV], dissemination and intensity features) in 30 cHL patients at baseline. EV-miR127-3p, EV-miR24-3p, sTARC, and several CBC parameters showed weak to strong correlations with MTV and dissemination features, but not with intensity features. Two other EV-miRNAs only showed weak correlations with PET features. Therefore, blood-based biomarkers may be complementary to PET features, which warrants further exploration of combining these biomarkers in prognostic models.

Exosomes take (germinal) center stage.

Efficient antibody production is a crucial step during immune responses leading to pathogen clearance and neutralization. Immune synapses, contact points between T and B lymphocytes in the presence of an antigen, are necessary to initiate the proliferation and differentiation of B cells in the germinal center. In this issue of EMBO Reports, Fernández-Messina et al [1] present evidence of microRNA transfer from T to B cells via exosomes during synapse formation and highlight the crucial role of these exosomes for germinal center formation and the efficient production of antigen-specific antibodies.

Altered microRNA processing proteins in HPV-induced cancers.

High-risk human papilloma virus (hrHPV) infections are associated with the development of anogenital cancers, in particular cervical cancer, and a subset of head and neck cancers. Previous studies have shown that microRNAs (miRNAs) contribute to the development and progression of HPV-induced malignancies. miRNAs are small non-coding RNAs that exist as multiple length and sequence variants, termed isomiRs. Efficient processing of miRNAs and generation of isomiRs is accomplished by several processing proteins. Deregulation of Drosha, AGO2, and TENT2, among others, has been observed in HPV-induced cancers and was even found at the precancerous stage. This suggests that miRNA processing proteins may be involved during early cancer development and that the generated isomiRs could provide promising biomarkers for early cancer diagnosis.

Epstein-Barr-virus-encoded LMP2A induces primary epithelial cell migration and invasion: possible role in nasopharyngeal carcinoma metastasis.

Nonkeratinizing nasopharyngeal carcinomas (NPC) are >95% associated with the expression of the Epstein-Barr virus (EBV) LMP2A latent protein. However, the role of EBV, in particular, LMP2A, in tumor progression is not well understood. Using Affymetrix chips and a pattern-matching computational technique (neighborhood analysis), we show that the level of LMP2A expression in NPC biopsy samples correlates with that of a cellular protein, integrin-alpha-6 (ITGalpha6), that is associated with cellular migration in vitro and metastasis in vivo. We have recently developed a primary epithelial model from tonsil tissue to study EBV infection in epithelial cells. Here we report that LMP2A expression in primary tonsil epithelial cells causes them to become migratory and invasive, that ITGalpha6 RNA levels are up-regulated in epithelial cells expressing LMP2, and that ITGalpha6 protein levels are increased in the migrating cells. Blocking antibodies against ITGalpha6 abrogated LMP2-induced invasion through Matrigel by primary epithelial cells. Our results provide a link between LMP2A expression, ITGalpha6 expression, epithelial cell migration, and NPC metastasis and suggest that EBV infection may contribute to the high incidence of metastasis in NPC progression.

Epstein-Barr virus infection in ex vivo tonsil epithelial cell cultures of asymptomatic carriers.

Epstein-Barr virus (EBV) is found frequently in certain epithelial pathologies, such as nasopharyngeal carcinoma and oral hairy leukoplakia, indicating that the virus can infect epithelial cells in vivo. Recent studies of cell lines imply that epithelial cells may also play a role in persistent EBV infection in vivo. In this report, we show the establishment and characterization of an ex vivo culture model of tonsil epithelial cells, a likely site for EBV infection in vivo. Primary epithelial-cell cultures, generated from tonsil explants, contained a heterogeneous mixture of cells with an ongoing process of differentiation. Keratin expression profiles were consistent with the presence of cells from both surface and crypt epithelia. A small subset of cells could be latently infected by coculture with EBV-releasing cell lines, but not with cell-free virus. We also detected viral-DNA, -mRNA, and -protein expression in cultures from EBV-positive tonsil donors prior to in vitro infection. We conclude that these cells were either already infected at the time of explantation or soon after through cell-to-cell contact with B cells replicating EBV in the explant. Taken together, these findings suggest that the tonsil epithelium of asymptomatic virus carriers is able to sustain EBV infection in vivo. This provides an explanation for the presence of EBV in naso- and oropharyngeal pathologies and is consistent with epithelial cells playing a role in the egress of EBV during persistent infection.