Autophagosome-based strategy to monitor apparent tumor-specific CD8 T cells in patients with prostate cancer.

The immune system plays an essential role in eradicating cancer in concert with various treatment modalities. In the absence of autologous tumor material, no standardized method exists to assess T cell responses against the many antigens that may serve as cancer rejection antigens. Thus, development of methods to screen for therapy-induced anti-tumor responses is a high priority that could help tailor therapy.

Glimpse into the future: harnessing autophagy to promote anti-tumor immunity with the DRibbles vaccine.

Because the benefits of immune checkpoint blockade may be restricted to tumors with pre-existing immune recognition, novel therapies that facilitate de novo immune activation are needed. DRibbles is a novel multi-valent vaccine that is created by disrupting degradation of intracellular proteins by the ubiquitin proteasome system. The DRibbles vaccine is comprised of autophagosome vesicles that are enriched with defective ribosomal products and short-lived proteins, known tumor-associated antigens, mediators of innate immunity, and surface markers that encourage phagocytosis and cross-presentation by antigen presenting cells.

Cross-presentation of viral antigens in dribbles leads to efficient activation of virus-specific human memory T cells.

Background: Autophagy regulates innate and adaptive immune responses to pathogens and tumors. We have reported that autophagosomes derived from tumor cells after proteasome inhibition, DRibbles (Defective ribosomal products in blebs), were excellent sources of antigens for efficient cross priming of tumor-specific CD8⁺ T cells, which mediated regression of established tumors in mice. But the activity of DRibbles in human has not been reported.

Autophagy-assisted antigen cross-presentation: Autophagosome as the argo of shared tumor-specific antigens and DAMPs.

It is generally believed that most tumor antigens are passively released from either health or dying tumor cells as intact soluble antigens, peptide fragments complexed with heat shock proteins (HSPs), or packaged in secretary vesicles in the form of microparticles or exosomes. The passive release of tumor antigens is generally non-inflammatory and non-immunogenic; however, results from others and our laboratories suggest that autophagy is critically involved in immunogenic cell death.

TAF1 histone acetyltransferase activity in Sp1 activation of the cyclin D1 promoter.

A missense mutation within the histone acetyltransferase (HAT) domain of the TATA binding protein-associated factor TAF1 induces ts13 cells to undergo a late G(1) arrest and decreases cyclin D1 transcription. We have found that TAF1 mutants (Delta844-850 and Delta848-850, from which amino acids 844 through 850 and 848 through 850 have been deleted, respectively) deficient in HAT activity are unable to complement the ts13 defect in cell proliferation and cyclin D1 transcription. Chromatin immunoprecipitation assays revealed that histone H3 acetylation was reduced at the cyclin D1 promoter but not the c-fos promoter upon inactivation of TAF1 in ts13 cells.

SRC proximal and core promoter elements dictate TAF1 dependence and transcriptional repression by histone deacetylase inhibitors.

Histone deacetylase inhibitors (HDIs) induce cell cycle arrest, differentiation, or apoptosis in numerous cancer cell types both in vivo and in vitro. These dramatic effects are the result of a specific reprogramming of gene expression. However, the mechanism by which these agents activate the transcription of some genes, such as p21(WAF1), but repress others, such as cyclin D1, is currently unknown.

Transcription factor IID recruitment and Sp1 activation. Dual function of TAF1 in cyclin D1 transcription.

Cyclin D1 is an oncogene that regulates progression through the G(1) phase of the cell cycle. A temperature-sensitive missense mutation in the transcription factor TAF1/TAF(II)250 induces the mutant ts13 cells to arrest in late G(1) by decreasing transcription of cell cycle regulators, including cyclin D1. Here we provide evidence that TAF1 serves two independent functions, one at the core promoter and one at the upstream activating Sp1 sites of the cyclin D1 gene.