Person:

Kim, Hye-Jung

It has been reported that retinoic acid (RA) enhances regulatory T (T reg) cell conversion by inhibiting the secretion of cytokines that interfere with conversion. This report shows that these conclusions provide a partial explanation at best. First, RA not only interfered with cytokine secretion but also with the ability of these cytokines to inhibit T reg cell conversion of naive T cells. Furthermore, RA enhanced conversion even in the absence of inhibitory cytokines. The latter effect depended on the RA receptor α (RARα) but did not require Smad3, despite the fact that RA enhanced Smad3 expression. The RARα1 isoform was not essential for RA-dependent enhancement of transforming growth factor β–driven conversion, suggesting that conversion can also be mediated by RARα2. Interleukin (IL)-6 strongly reduced RARα expression levels such that a deficiency of the predominant RARα1 isoform leaves too little RARα2 for RA to inhibit the generation of Th17 cells in the presence of IL-6.

Antigen receptor editing—a process of secondary rearrangements of antigen receptor genes in autoreactive lymphocytes—is a well-established tolerance mechanism in B cells, whereas its role in T cells remains controversial. Here, we investigated this issue using a novel Tcra knock-in locus, which ensured appropriate timing of TCRα expression and allowed secondary rearrangements. Under these conditions the only response to self-antigen that could be unambiguously identified was negative selection of CD4/CD8 double positive thymocytes. No evidence could be obtained for antigen-induced TCR editing, whereas replacement of the transgenic TCRα chain by ongoing gene rearrangement occurred in some cells irrespective of the presence or absence of self-antigen.

Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies1,2. Pharmacologic inhibitors of CDK4/6 have shown significant activity against several solid tumors3,4. Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma (RB) tumor suppressor, inducing G1 cell cycle arrest in tumor cells5. Here, we use murine models of breast carcinoma and other solid tumors to show that selective CDK4/6 inhibitors not only induce tumor cell cycle arrest, but also promote anti-tumor immunity. We confirm this phenomenon through transcriptomic analysis of serial biopsies from a clinical trial of CDK4/6 inhibitor treatment for breast cancer. The enhanced anti-tumor immune response has two underpinnings. First, CDK4/6 inhibitors activate tumor cell expression of endogenous retroviral elements, thus increasing intracellular levels of double-stranded RNA. This in turn stimulates production of type III interferons and hence enhances tumor antigen presentation. Second, CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells (Tregs). Mechanistically, the effects of CDK4/6 inhibitors on both tumor cells and Tregs are associated with reduced activity of the E2F target, DNA methyltransferase 1. Ultimately, these events promote cytotoxic T cell-mediated clearance of tumor cells, which is further enhanced by the addition of immune checkpoint blockade. Our findings indicate that CDK4/6 inhibitors increase tumor immunogenicity and provide rationale for new combination regimens comprising CDK4/6 inhibitors and immunotherapies as anti-cancer treatment.

Tumour-associated antigens (TAAs) comprise a large collection of non-mutated cellular antigens recognized by T cells in human and murine cancers. Their potential as immunotherapy targets has been explored for over two decades, yet the genesis of TAA-specific T cells remains elusive. While tumour cells may be an important source of TAAs for T cell priming, several recent studies suggest that infection with some viruses including Epstein-Barr virus (EBV) and influenza virus can elicit T cell responses against abnormally expressed cellular antigens that function as TAAs. However, the cellular and molecular basis of such responses remains undefined. Here, we show that expression of the EBV signaling protein LMP1 in B cells provokes T cell responses to multiple TAAs. LMP1 signaling leads to overexpression of many cellular antigens previously shown to be TAAs, their presentation on MHC-I and -II (mainly through the endogenous pathway), and the upregulation of costimulatory ligands CD70 and OX40L, thereby inducing potent cytotoxic CD4+ and CD8+ T cell responses. These findings delineate a novel mechanism of infection-induced anti-tumour immunity. Furthermore, by ectopically expressing LMP1 in patient tumour B cells and thereby empowering them to prime T cells, we develop a general approach for rapid production of autologous cytotoxic CD4+ T cells against a broad array of endogenous tumour antigens, such as TAAs and neoantigens, for treating B-cell malignancies. This work stresses the need to revisit classical concepts concerning viral and tumour immunity, which will be critical to fully understand the impact of common infections on human health and to improve the rational design of immune approaches for cancers.