To understand why cancer vaccine-induced T cells often fail to eradicate tumors, we studied immune responses in mice vaccinated with gp100 melanoma peptide in incomplete Freund’s adjuvant (IFA), commonly used in clinical cancer vaccine trials. Peptide/IFA vaccination primed tumor-specific CD8+ T cells, which accumulated not in tumors but at the persisting, antigen-rich vaccination site. Once there, primed T cells became dysfunctional and underwent antigen-driven, Interferon-γ (IFN-γ) and Fas ligand (FasL)-mediated apoptosis, resulting in hyporesponsiveness to subsequent vaccination. Provision of anti-CD40 antibody, Toll-like receptor 7 (TLR7) agonist and interleukin-2 (IL-2) reduced T cell apoptosis but did not prevent vaccination site sequestration. A non-persisting vaccine formulation shifted T cell localization towards tumors, inducing superior anti-tumor activity while reducing systemic T cell dysfunction and promoting memory formation. Persisting peptide/IFA vaccine depots can induce specific T cell sequestration, dysfunction and deletion at vaccination sites; short-lived formulations may overcome these limitations and result in greater therapeutic efficacy of peptide-based cancer vaccines.

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Regulatory T cells (T reg ) suppress autoreactive immune responses and limit the efficacy of tumor vaccines; however, it remains a challenge to selectively eliminate or inhibit T reg . In this study, A20, a negative regulator of the TLR and TNFR signaling pathways, was found to play a critical role in controlling the maturation, cytokine production, and immunostimulatory potency of dendritic cells (DC). A20-silenced DCs with the spontaneous and enhanced expression of costimulatory molecules and proinflammatory cytokines have contrary effects on T cell subsets: inhibiting T reg and hyperactivating cytotoxic T lymphocytes and T-helpers that produced IL-6 and TNFα, infiltrated tumors, and were refractory to T reg -mediated suppression. Hence, this study not only identifies A20 as a critical antigen presentation attenuator in control of antitumor immune responses during both the priming and effector phases, but also provides a novel strategy to supersede T reg -mediated suppression in an antigen-specific manner, reducing the need to directly target T reg .

Epigenetic histone modifications play critical roles in the control of gene transcription. Recently, an increasing number of histone H2A deubiquitinases have been identified and characterized. However, the physiological functions for this entire group of histone H2A deubiquitinases remain unknown. In this study, we revealed that the histone H2A deubiquitinase MYSM1 plays an essential and intrinsic role in early B-cell development. MYSM1 deficiency results in a block in early B-cell commitment and a defect of B-cell progenitors in expression of EBF1 and other B-lymphoid genes. We further demonstrated that MYSM1 de-represses EBF1 transcription in B-cell progenitors by orchestrating histone modifications and transcription factor recruitment to the EBF1 locus. Thus, this study not only uncovers the essential role for MYSM1 in gene transcription during early B cell development, but also underscores the biological significance of reversible epigenetic histone H2A ubiquitination.