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Anti-PD-1 antibody-mediated activation of type 17 T-cells undermines checkpoint inhibitor therapy in the LSL-KrasG12D murine lung cancer model. Herein, we establish that the Th17 subset is the primary driver of resistance to therapy demonstrate that the ontogeny of dysplasia-associated Th17 cells is driven by microbiota-conditioned macrophages; and identify the IL-17-COX-2-PGE2 axis as the mediator of CD8+ cytotoxic T-lymphocyte de-sensitization to checkpoint inhibitor therapy. Specifically, anti-PD-1 treatment of LSL-KrasG12D mice, in which CD4+ T-cells were deficient for RORc, resulted in a 60% increase in CTL cytotoxicity and a 2.5-fold reduction in tumor burden confirming the critical role of Th17 cells in resistance to therapy. Lung-specific depletion of microbiota reduced Th17 cell prevalence and tumor burden by 5- and 2.5-fold, respectively; establishing a link between microbiota and Th17 cell-driven tumorigenesis. Importantly, lung macrophages from microbiota sufficient, but not from microbiota-deficient, mice polarized naïve CD4+ T-cells to a Th17 phenotype, highlighting their role in bridging microbiota and Th17 immunity. Further, treatment with anti-PD-1 enhanced COX-2 and PGE2 levels, whereas neutralization of IL-17 diminished this effect. In contrast, inhibition of COX-2 rescued CTL activity and restored tumor suppression in anti-PD-1-treated mice, revealing the molecular basis of IL-17-mediated resistance to checkpoint blockade. Clinical implications of these findings are discussed. [ABSTRACT FROM AUTHOR]

Natural SIV infection of sooty mangabeys (SMs) is nonprogressive despite chronic virus replication. Strikingly, it is characterized by low levels of immune activation, while pathogenic SIV infection of rhesus macaques (RMs) is associated with chronic immune activation. To elucidate the mechanisms underlying this intriguing phenotype, we used high-density oligonucleotide microarrays to longitudinally assess host gene expression in SIV-infected SMs and RMs. We found that acute SIV infection of SMs was consistently associated with a robust innate immune response, including widespread upregulation of IFN-stimulated genes (ISGs) in blood and lymph nodes. While SMs exhibited a rapid resolution of ISG expression and immune activation, both responses were observed chronically in RMs. Systems biology analysis indicated that expression of the lymphocyte inhibitory receptor LAG3, a marker of T cell exhaustion, correlated with immune activation in SIV-infected RMs but not SMs. Our findings suggest that active immune regulatory mechanisms, rather than intrinsically attenuated innate immune responses, underlie the low levels of immune activation characteristic of SMs chronically infected with SIV., Introduction HIV infection is characterized by progressive depletion of [CD4.sup.+] T cells that eventually results in clinically significant immunodeficiency. Although development of AIDS occurs years after primary HIV infection, it [...]

Although there has been great progress in treating human immunodeficienry virns 1 (HIV-1) infection (1), preventing transmission has thus far proven an elusive goal. Indeed, recent trials of a candidate vaccine and microbicide have been disappointing, both for want of efficacy and concerns about increased rates of transmission (2-4). Nonetheless, studies of vaginal transmission in the simian immunodeficienry virus (SIV)-rhesus macaque (Macacca mulatta) model point to opportunities at the earliest stages of infection in which a vaccine or microbicide might be protective, by limiting the expansion of infected founder populations at the portal of entrys (5-6). Here we show in this SIV-macaque model, that an outside-in endocervical mucosal signalling system, involving MIP-3 α (also known as CCL20), plasmarytoid dendritic cells and [CCR5.sup.+] cell-attracting chemokines produced by these cells, in combination with the innate immune and inflammatory responses to infection in both cervix and vagina, recrnits [CD4.sup.+] T cells to fuel this obligate expansion. We then show that glycerol monolaurate--a widely used antimicrobial compound (7) with inhibitory activity against the production of MIP-3α and other proinflammatory cytokines (8)--can inhibit mucosal signalling and the innate and inflammatory response to HIV-1 and SIV in vitro, and in vivo it can protect rhesus macaques from acute infection despite repeated intra-vaginal exposure to high doses of SIV. This new approach, plausibly linked to interfering with innate host responses that recruit the target cells necessary to establish systemic infection, opens a promising new avenue for the development of effective interventions to block HIV-1 mucosal transmission., To understand how SIV infection in a small founder population of cells at the portal of entry transitions in less than two weeks to systemic infection, with massive levels of [...]