Key Points: Blockade of CD7 expression with a novel method, combined with a second-generation CAR, results in highly potent anti-CD7 CAR T cells. This practical strategy provides a new treatment option for patients with high-risk T-cell malignancies, including ETP-ALL.

Key Points: Newly designed PEBLs prevent surface expression of T-cell receptor in T cells without affecting their function. Combined with chimeric antigen receptors, PEBLs can rapidly generate powerful antileukemic T cells without alloreactivity.

Mucosa-associated invariant T (MAIT) cells are abundant antimicrobial T cells in humans and recognize antigens derived from the microbial riboflavin biosynthetic pathway presented by the MHC-Ib-related protein (MR1). However, the mechanisms responsible for MAIT cell antimicrobial activity are not fully understood, and the efficacy of these mechanisms against antibiotic resistant bacteria has not been explored. Here, we show that MAIT cells mediate MR1-restricted antimicrobial activity against Escherichia coli clinical strains in a manner dependent on the activity of cytolytic proteins but independent of production of pro-inflammatory cytokines or induction of apoptosis in infected cells. The combined action of the pore-forming antimicrobial protein granulysin and the serine protease granzyme B released in response to T cell receptor (TCR)-mediated recognition of MR1-presented antigen is essential to mediate control against both cell-associated and free-living, extracellular forms of E. coli. Furthermore, MAIT cell-mediated bacterial control extends to multidrug-resistant E. coli primary clinical isolates additionally resistant to carbapenems, a class of last resort antibiotics. Notably, high levels of granulysin and granzyme B in the MAIT cell secretomes directly damage bacterial cells by increasing their permeability, rendering initially resistant E. coli susceptible to the bactericidal activity of carbapenems. These findings define the role of cytolytic effector proteins in MAIT cell-mediated antimicrobial activity and indicate that granulysin and granzyme B synergize to restore carbapenem bactericidal activity and overcome carbapenem resistance in E. coli.

A vast majority of the population worldwide are asymptomatic carriers of Epstein-Barr Virus (EBV). However, some infected individuals eventually develop EBV-related cancers, including Nasopharyngeal Carcinoma (NPC). NPC is one of the most common EBV-associated epithelial cancers, and is highly prevalent in Southern China and Southeast Asia. While NPC is highly sensitive to radiotherapy and chemotherapy, there is a lack of effective and durable treatment among the 15%–30% of patients who subsequently develop recurrent disease. Natural Killer (NK) cells are natural immune lymphocytes that are innately primed against virus-infected cells and nascent aberrant transformed cells. As EBV is found in both virally infected and cancer cells, it is of interest to examine the NK cells’ role in both EBV infection and EBV-associated NPC. Herein, we review the current understanding of how EBV-infected cells are cleared by NK cells, and how EBV can evade NK cell-mediated elimination in the context of type II latency in NPC. Next, we summarize the current literature about NPC and NK cell biology. Finally, we discuss the translational potential of NK cells in NPC. This information will deepen our understanding of host immune interactions with EBV-associated NPC and facilitate development of more effective NK-mediated therapies for NPC treatment.

In adoptive T-cell immunotherapy of cancer, expansion and persistence of effector cells is a key determinant of response. We tested whether T lymphocytes could be rendered sensitive to erythropoietin (Epo) through ectopic expression of its wild-type receptor or a truncated form (EpoRm), which augments Epo signaling in erythrocyte progenitors. Both receptors could be expressed in human T lymphocytes; Epo ligation induced STAT5 phosphorylation, which was abrogated by nontoxic concentrations of the JAK1/2 inhibitor ruxolitinib. EpoRm had higher expression and triggered more potent stimulation than its wild-type counterpart, including superior T-cell survival and proliferation. Using a bicistronic vector, we expressed EpoRm together with an anti–CD19-41BB-CD3ζ chimeric antigen receptor (CAR), while maintaining the functions of each receptor. In the presence of Epo, EpoRm-CAR T cells had greater ex vivo expansion than CAR T cells and killed CD19+ leukemic cells more effectively in long-term cultures. In immunodeficient mice, physiologic levels of murine Epo were sufficient to preferentially expand EpoRm-CAR T cells, yielding a significantly higher antileukemic activity. Thus, outfitting adoptive T cells with EpoRm should yield greater effector-to-target ratios with a smaller number of infused cells; Epo or ruxolitinib administration could be used to adjust their levels postinfusion, maximizing antitumor activity and minimizing toxicity.