SUMMARY Therapeutic antibodies targeting programmed cell death-1 (PD-1) activate tumor-specific immunity and have shown remarkable efficacy in the treatment of melanoma. Yet, little is known about tumor cell-intrinsic PD-1 pathway effects. Here we show that murine and human melanomas contain PD-1-expressing cancer subpopulations and demonstrate that melanoma cell-intrinsic PD-1 promotes tumorigenesis, even in mice lacking adaptive immunity. PD-1 inhibition on melanoma cells by RNA interference, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, as does engagement of melanoma-PD-1 by its ligand, PD-L1, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuate growth of PD-1-positive melanomas. Mechanistically, the melanoma-PD-1 receptor modulates downstream effectors of mTOR signaling. Our results identify melanoma cell-intrinsic functions of the PD-1:PD-L1 axis in tumor growth and suggest that blocking melanoma-PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy.

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T helper type 9 (TH9) cells can mediate tumor immunity and participate in autoimmune and allergic inflammation in mice but little is known about the TH9 cells that develop in vivo in humans. We isolated T cells from human blood and tissues and found that most memory TH9 cells were skin-tropic or skin-resident. Human TH9 cells co-expressed TNFα and granzyme B, lacked coproduction of TH1/TH2/TH17 cytokines and many were specific for C. albicans. IL-9 production was transient and preceded the up-regulation of other inflammatory cytokines. Blocking studies demonstrated that IL-9 was required for maximal production of IFN-γ, IL-9, IL-13, and IL-17 by skin tropic T cells. IL-9 producing T cells were increased in the skin lesions of psoriasis, suggesting these cells may contribute to human inflammatory skin disease. Our results indicate human TH9 cells are a discrete T cell subset, many are tropic for the skin, and although they may function normally to protect against extracellular pathogens, aberrant activation of these cells may contribute to inflammatory diseases of the skin.

No abstract

Sepsis, sepsis-induced hyperinflammation and subsequent sepsis-associated immunosuppression (SAIS) are important causes of death. Here we show in humans that the loss of the major reactive oxygen species (ROS) scavenger, glutathione (GSH), during SAIS directly correlates with an increase in the expression of activating transcription factor 3 (ATF3). In endotoxin-stimulated monocytes, ROS stress strongly superinduced NF-E2–related factor 2 (NRF2)–dependent ATF3. In vivo, this ROS-mediated superinduction of ATF3 protected against endotoxic shock by inhibiting innate cytokines, as Atf3−/− mice remained susceptible to endotoxic shock even under conditions of ROS stress. Although it protected against endotoxic shock, this ROS-mediated superinduction of ATF3 caused high susceptibility to bacterial and fungal infections through the suppression of interleukin 6 (IL-6). As a result, Atf3−/− mice were protected against bacterial and fungal infections, even under conditions of ROS stress, whereas Atf3−/−Il6−/− mice were highly susceptible to these infections. Moreover, in a model of SAIS, secondary infections caused considerably less mortality in Atf3−/− mice than in wild-type mice, indicating that ROS-induced ATF3 crucially determines susceptibility to secondary infections during SAIS.

Purpose In leukemic CTCL (L-CTCL) malignant T cells accumulate in the blood and give rise to widespread skin inflammation. Patients have intense pruritus, increased IgE, decreased Th1 responses and most die from infection. Depleting malignant T cells while preserving normal immunity is a clinical challenge. L-CTCL has been variably described as a malignancy of regulatory, Th2 and Th17 cells. Experimental design We analyzed phenotype and cytokine production in malignant and benign L-CTCL T cells, characterized the effects of malignant T cells on healthy T cells and studied the immunomodulatory effects of treatment modalities in L-CTCL patients. Results 12/12 L-CTCL patients overproduced Th2 cytokines. Remaining benign T cells were also strongly Th2 biased, suggesting a global Th2 skewing of the T cell repertoire. Culture of benign T cells away from the malignant clone reduced Th2 and enhanced Th1 responses but separate culture had no effect on malignant T cells. Co-culture of healthy T cells with L-CTCL T cells reduced IFNγ production and neutralizing antibodies to IL-4 and IL-13 restored Th1 responses. In patients, enhanced Th1 responses were observed following a variety of treatment modalities that reduced malignant T cell burden. Conclusions A global Th2 bias exists in both benign and malignant T cells in L-CTCL and may underlie the infectious susceptibility of patients. Th2 cytokines from malignant cells strongly inhibited Th1 responses. Our results suggest therapies that inhibit Th2 cytokine activity, by virtue of their ability to improve Th1 responses, may have the potential to enhance both anti-cancer and anti-pathogen responses.

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Background: Interleukin (IL)-23 is involved in the pathogenesis of the chronic inflammatory Crohn disease. Pyoderma gangrenosum (PG) is often associated with and can even be the first manifestation of this disease and has abundant neutrophilic infiltration. Because IL-23 plays a critical role in driving inflammation associated with IL-17 production and especially neutrophil recruitment, we suspect that PG might be driven by a pathogenetic mechanism similar to that of inflammatory bowel diseases or psoriasis. Observations: Tissue sample analysis showed highly elevated expression of IL-23 on both transcriptional and protein level in a recalcitrant PG lesion. On the basis on these data, a treatment targeting the p40 subunit of the heterodimeric IL-23 with the monoclonal antibody ustekinumab was started. Therapy with ustekinumab resulted in a significant decrease of IL-23 expression in PG and healing after 14 weeks of treatment. No relapse occurred in a 6-month follow-up period. Conclusions: Our data provide evidence of an IL-23dominated inflammatory infiltrate in PG. This might specify a new concept for PG pathophysiology and suggests a possibility for using ustekinumab as a therapeutic agent in this disease.