Targeting VCP potentiates immune checkpoint therapy for colorectal cancer

Summary: Immune checkpoint blockade therapies are still ineffective for most patients with colorectal cancer (CRC). Immunogenic cell death (ICD) enables the release of key immunostimulatory signals to drive efficient anti-tumor immunity, which could be used to potentiate the effects of immune checkpoint inhibitors. Here, we showed that inhibition of valosin-containing protein (VCP) elicits ICD in CRC. Meanwhile, VCP inhibitor upregulates PD-L1 expression and compromises anti-tumor immunity in vivo. Mechanistically, VCP transcriptionally regulates PD-L1 expression in a JAK1-dependent manner. Combining VCP inhibitor with anti-PD1 remodels tumor immune microenvironment and reduces tumor growth in mouse models of CRC. Addition of oncolytic virus further augments the therapeutic activity of the combination regimen. Our study shows the molecular mechanism for regulating PD-L1 expression by VCP and suggests that inhibition of VCP has the potential to increase the efficacy of immunotherapy in CRC

The impact of viral mutations on recognition by SARS-CoV-2 specific T cells

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity