Singh et al. examined microRNA expression and physiological requirements in type 2 innate lymphoid cells (ILC2s). The miR-17∼92 cluster promotes ILC2 growth, cytokine expression, and function in allergic inflammation.

FOXP3+ regulatory T cells (Treg) play a critical role in mediating tolerance to self-antigens and can repress antitumor immunity through multiple mechanisms. Therefore, targeted depletion of tumor-resident Tregs is warranted to promote effective antitumor immunity while preserving peripheral homeostasis. Here, we propose the chemokine receptor CCR8 as one such optimal tumor Treg target. CCR8 was expressed by Tregs in both murine and human tumors, and unlike CCR4, a Treg depletion target in the clinic, CCR8 was selectively expressed on suppressive tumor Tregs and minimally expressed on proinflammatory effector T cells (Teff). Preclinical mouse tumor modeling showed that depletion of CCR8+ Tregs through an FcyR-engaging anti-CCR8 antibody, but not blockade, enabled dose-dependent, effective, and long-lasting antitumor immunity that synergized with PD-1 blockade. This depletion was tumor Treg-restricted, sparing CCR8+ T cells in the spleen, thymus, and skin of mice. Importantly, Fc-optimized, nonfucosylated (nf) anti-human CCR8 antibodies specifically depleted Tregs and not Teffs in ex vivo tumor cultures from primary human specimens. These findings suggest that anti–CCR8-nf antibodies may deliver optimal tumor-targeted Treg depletion in the clinic, providing long-term antitumor memory responses while limiting peripheral toxicities. Significance: These findings show that selective depletion of regulatory T cells with an anti-CCR8 antibody can improve antitumor immune responses as a monotherapy or in combination with other immunotherapies.

T helper (Th)17 cell responses orchestrate immunity against extracellular pathogens, but also underlie autoimmune disease pathogenesis. Here, we uncovered a distinct and critical role for miR-18a in limiting Th17 cell differentiation. miR-18a was the most dynamically upregulated miRNA of the miR-17∼92 cluster in activated T cells. miR-18a deficiency enhanced CCR6+RORγt+ Th17 cell differentiation in vitro and increased the number of tissue Th17 cells expressing CCR6, RORγt and IL-17A in airway inflammation models in vivo. Sequence-specific miR-18 inhibitors increased CCR6 and RORγt expression in both mouse and human CD4+ T cells, revealing functional conservation. miR-18a directly targeted Smad4, Hif1a, and Rora, all key transcription factors in the Th17 cell gene expression program. These findings indicate that activating signals influence the outcome of T helper cell differentiation via differential regulation of mature miRNAs within a common cluster.

Using newer vaccine platforms which have been effective against malaria in rodent models, we tested five immunization regimens against Plasmodium knowlesi in rhesus monkeys. All vaccines included the same four P. knowlesi antigens: the pre-erythrocytic antigens CSP, SSP2, and erythrocytic antigens AMA1, MSP1. We used four vaccine platforms for prime or boost vaccinations: plasmids (DNA), alphavirus replicons (VRP), attenuated adenovirus serotype 5 (Ad), or attenuated poxvirus (Pox). These four platforms combined to produce five different prime/boost vaccine regimens: Pox alone, VRP/Pox, VRP/Ad, Ad/Pox, and DNA/Pox. Five rhesus monkeys were immunized with each regimen, and five Control monkeys received a mock vaccination. The time to complete vaccinations was 420 days. All monkeys were challenged twice with 100 P. knowlesi sporozoites given IV. The first challenge was given 12 days after the last vaccination, and the monkeys receiving the DNA/Pox vaccine were the best protected, with 3/5 monkeys sterilely protected and 1/5 monkeys that self-cured its parasitemia. There was no protection in monkeys that received Pox malaria vaccine alone without previous priming. The second sporozoite challenge was given 4 months after the first. All 4 monkeys that were protected in the first challenge developed malaria in the second challenge. DNA, VRP and Ad5 vaccines all primed monkeys for strong immune responses after the Pox boost. We discuss the high level but short duration of protection in this experiment and the possible benefits of the long interval between prime and boost.

Potent anti‐tumor T cell response and efficient intratumoral T cell infiltration are the major challenges for therapeutic cancer vaccines. To address these issues, a nanovaccine system is designed to promote anti‐tumor T cell responses, and intratumoral infiltration is examined in various murine tumor models. Subcutaneous vaccination with nanodiscs carrying human papillomavirus (HPV)‐16 E7 antigen elicits as high as ∼32% E7‐specific CD8α+ T cell responses in circulation, representing a 29‐fold improvement over the soluble peptide vaccination. Importantly, nanodisc vaccination also promotes robust intratumoral T cell infiltration and eliminates HPV16 E6/E7‐expressing TC‐1 tumors at mucosal sites, including lungs, inner lip, and intravaginal tissues. In a benchmark study with a live Listeria vaccine combined with anti‐PD‐1 IgG, nanodiscs plus anti‐PD‐1 immune checkpoint blockade elicits comparable levels of T cell responses with anti‐tumor efficacy. Furthermore, compared with Complete Freund's Adjuvant combined with tetanus toxoid, nanodisc vaccination in HLA‐A02 mice generates >200‐fold stronger IFN‐γ+ T cell responses against a neoantigen from an HLA‐A02 melanoma patient. Overall, these results show that the nanodisc system is a promising cancer vaccine platform for inducing anti‐tumor T cell responses.