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Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations.

SHP2 is a ubiquitous tyrosine phosphatase involved in regulating both tumor and immune cell signaling. In this study, we discovered a novel immune modulatory function of SHP2. Targeting this protein with allosteric SHP2 inhibitors promoted anti-tumor immunity, including enhancing T cell cytotoxic function and immune-mediated tumor regression. Knockout of SHP2 using CRISPR/Cas9 gene editing showed that targeting SHP2 in cancer cells contributes to this immune response. Inhibition of SHP2 activity augmented tumor intrinsic IFNγ signaling resulting in enhanced chemoattractant cytokine release and cytotoxic T cell recruitment, as well as increased expression of MHC Class I and PD-L1 on the cancer cell surface. Furthermore, SHP2 inhibition diminished the differentiation and inhibitory function of immune suppressive myeloid cells in the tumor microenvironment. SHP2 inhibition enhanced responses to anti-PD-1 blockade in syngeneic mouse models. Overall, our study reveals novel functions of SHP2 in tumor immunity and proposes that targeting SHP2 is a promising strategy for cancer immunotherapy.

CD4⁺ T helper 1 ($\\text{T}_{\\text{H}}1$) cells are important mediators of inflammation and are regulated by numerous pathways, including the negative immune receptor Tim-3. We found that Tim-3 is constitutively expressed on cells of the innate immune system in both mice and humans, and that it can synergize with Toll-like receptors. Moreover, an antibody agonist of Tim-3 acted as an adjuvant during induced immune responses, and Tim-3 ligation induced distinct signaling events in T cells and dendritic cells; the latter finding could explain the apparent divergent functions of Tim-3 in these cell types. Thus, by virtue of differential expression on innate versus adaptive immune cells, Tim-3 can either promote or terminate$\\text{T}_{\\text{H}}1$immunity and may be able to influence a range of inflammatory conditions.

The recent discovery of CD4(+) T cells characterized by secretion of interleukin (IL)-17 (T(H)17 cells) and the naturally occurring regulatory FOXP3(+) CD4 T cell (nT(reg)) has had a major impact on our understanding of immune processes not readily explained by the T(H)1/T(H)2 paradigm. T(H)17 and nT(reg) cells have been implicated in the pathogenesis of human autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis. Our recent data and the work of others demonstrated that transforming growth factor-beta (TGF-beta) and IL-6 are responsible for the differentiation of naive mouse T cells into T(H)17 cells, and it has been proposed that IL-23 may have a critical role in stabilization of the T(H)17 phenotype. A second pathway has been discovered in which a combination of TGF-beta and IL-21 is capable of inducing differentiation of mouse T(H)17 cells in the absence of IL-6 (refs 6-8). However, TGF-beta and IL-6 are not capable of differentiating human T(H)17 cells and it has been suggested that TGF-beta may in fact suppress the generation of human T(H)17 cells. Instead, it has been recently shown that the cytokines IL-1beta, IL-6 and IL-23 are capable of driving IL-17 secretion in short-term CD4(+) T cell lines isolated from human peripheral blood, although the factors required for differentiation of naive human CD4 to T(H)17 cells are still unknown. Here we confirm that whereas IL-1beta and IL-6 induce IL-17A secretion from human central memory CD4(+) T cells, TGF-beta and IL-21 uniquely promote the differentiation of human naive CD4(+) T cells into T(H)17 cells accompanied by expression of the transcription factor RORC2. These data will allow the investigation of this new population of T(H)17 cells in human inflammatory disease.

Cytokines involved in T H 17 cell differentiation T H 17 cells (a subset of interleukin (IL)-17-producing T helper cells) are thought to contribute to the pathogenesis of a number of human autoimmune diseases. This study examines which cytokines are required for the production of IL-17A by memory and naive human CD4 T cells. The data demonstrate that transforming growth factor-β (TGF-β) is critical for the differentiation of T H 17 cells from highly purified naive CD4 + T cells, but not necessary for induction of IL-17 from committed memory CD4 + T cells. The T H 17 pathway is thought to contribute to the pathogenesis of a number of human autoimmune diseases. This study examines which cytokines are required for the production of IL-17A by memory and naive human CD4 + T cells. The recent discovery of CD4 + T cells characterized by secretion of interleukin (IL)-17 (T H 17 cells) and the naturally occurring regulatory FOXP3 + CD4 T cell (nT reg ) has had a major impact on our understanding of immune processes not readily explained by the T H 1/T H 2 paradigm. T H 17 and nT reg cells have been implicated in the pathogenesis of human autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis 1 , 2 . Our recent data and the work of others demonstrated that transforming growth factor-β (TGF-β) and IL-6 are responsible for the differentiation of naive mouse T cells into T H 17 cells, and it has been proposed that IL-23 may have a critical role in stabilization of the T H 17 phenotype 3 , 4 , 5 . A second pathway has been discovered in which a combination of TGF-β and IL-21 is capable of inducing differentiation of mouse T H 17 cells in the absence of IL-6 (refs 6–8 ). However, TGF-β and IL-6 are not capable of differentiating human T H 17 cells 2 , 9 and it has been suggested that TGF-β may in fact suppress the generation of human T H 17 cells 10 . Instead, it has been recently shown that the cytokines IL-1β, IL-6 and IL-23 are capable of driving IL-17 secretion in short-term CD4 + T cell lines isolated from human peripheral blood 11 , although the factors required for differentiation of naive human CD4 to T H 17 cells are still unknown. Here we confirm that whereas IL-1β and IL-6 induce IL-17A secretion from human central memory CD4 + T cells, TGF-β and IL-21 uniquely promote the differentiation of human naive CD4 + T cells into T H 17 cells accompanied by expression of the transcription factor RORC2. These data will allow the investigation of this new population of T H 17 cells in human inflammatory disease.

Cytokines involved in T.sub.H17 cell differentiation T.sub.H17 cells (a subset of interleukin (IL)-17-producing T helper cells) are thought to contribute to the pathogenesis of a number of human autoimmune diseases. This study examines which cytokines are required for the production of IL-17A by memory and naive human CD4 T cells. The data demonstrate that transforming growth factor-[beta] (TGF-[beta]) is critical for the differentiation of T.sub.H17 cells from highly purified naive CD4.sup.+ T cells, but not necessary for induction of IL-17 from committed memory CD4.sup.+ T cells. The T.sub.H17 pathway is thought to contribute to the pathogenesis of a number of human autoimmune diseases. This study examines which cytokines are required for the production of IL-17A by memory and naive human CD4.sup.+ T cells. The recent discovery of CD4.sup.+ T cells characterized by secretion of interleukin (IL)-17 (T.sub.H17 cells) and the naturally occurring regulatory FOXP3.sup.+ CD4 T cell (nT.sub.reg) has had a major impact on our understanding of immune processes not readily explained by the T.sub.H1/T.sub.H2 paradigm. T.sub.H17 and nT.sub.reg cells have been implicated in the pathogenesis of human autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis.sup.1,2. Our recent data and the work of others demonstrated that transforming growth factor-[beta] (TGF-[beta]) and IL-6 are responsible for the differentiation of naive mouse T cells into T.sub.H17 cells, and it has been proposed that IL-23 may have a critical role in stabilization of the T.sub.H17 phenotype.sup.3,4,5. A second pathway has been discovered in which a combination of TGF-[beta] and IL-21 is capable of inducing differentiation of mouse T.sub.H17 cells in the absence of IL-6 (refs 6-8). However, TGF-[beta] and IL-6 are not capable of differentiating human T.sub.H17 cells.sup.2,9 and it has been suggested that TGF-[beta] may in fact suppress the generation of human T.sub.H17 cells.sup.10. Instead, it has been recently shown that the cytokines IL-1[beta], IL-6 and IL-23 are capable of driving IL-17 secretion in short-term CD4.sup.+ T cell lines isolated from human peripheral blood.sup.11, although the factors required for differentiation of naive human CD4 to T.sub.H17 cells are still unknown. Here we confirm that whereas IL-1[beta] and IL-6 induce IL-17A secretion from human central memory CD4.sup.+ T cells, TGF-[beta] and IL-21 uniquely promote the differentiation of human naive CD4.sup.+ T cells into T.sub.H17 cells accompanied by expression of the transcription factor RORC2. These data will allow the investigation of this new population of T.sub.H17 cells in human inflammatory disease.

The recent discovery of CD4 super(+) T cells characterized by secretion of interleukin (IL)-17 (T sub(H)17 cells) and the naturally occurring regulatory FOXP3 super(+) CD4 T cell (nT sub(reg)) has had a major impact on our understanding of immune processes not readily explained by the T sub(H)1/T sub(H)2 paradigm. T sub(H)17 and nT sub(reg) cells have been implicated in the pathogenesis of human autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis. Our recent data and the work of others demonstrated that transforming growth factor-beta (TGF-beta) and IL-6 are responsible for the differentiation of naive mouse T cells into T sub(H)17 cells, and it has been proposed that IL-23 may have a critical role in stabilization of the T sub(H)17 phenotype. A second pathway has been discovered in which a combination of TGF-beta and IL-21 is capable of inducing differentiation of mouse T sub(H)17 cells in the absence of IL-6. However, TGF-beta and IL-6 are not capable of differentiating human T sub(H)17 cells and it has been suggested that TGF-beta may in fact suppress the generation of human T sub(H)17 cells. Instead, it has been recently shown that the cytokines IL-1beta, IL-6 and IL-23 are capable of driving IL-17 secretion in short-term CD4 super(+) T cell lines isolated from human peripheral blood, although the factors required for differentiation of naive human CD4 to T sub(H)17 cells are still unknown. Here we confirm that whereas IL-1beta and IL-6 induce IL-17A secretion from human central memory CD4 super(+) T cells, TGF- beta and IL-21 uniquely promote the differentiation of human naive CD4 super(+) T cells into T sub(H)17 cells accompanied by expression of the transcription factor RORC2. These data will allow the investigation of this new population of T sub(H)17 cells in human inflammatory disease.

The recent discovery of CD4^sup +^ T cells characterized by secretion of interleukin (IL)-17 (T^sub H^17 cells) and the naturally occurring regulatory FOXP3^sup +^ CD4 T cell (nT^sub reg^) has had a major impact on our understanding of immune processes not readily explained by the T^sub H^1/T^sub H^2 paradigm. T^sub H^17 and nT^sub reg^ cells have been implicated in the pathogenesis of human autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis. Our recent data and the work of others demonstrated that transforming growth factor-β (TGF-β) and IL-6 are responsible for the differentiation of naive mouse T cells into T^sub H^17 cells, and it has been proposed that IL-23 may have a critical role in stabilization of the T^sub H^17 phenotype. A second pathway has been discovered in which a combination of TGF-β and IL-21 is capable of inducing differentiation of mouse T^sub H^17 cells in the absence of IL-6 (refs 6-8). However, TGF-β and IL-6 are not capable of differentiating human T^sub H^17 cells and it has been suggested that TGF-β may in fact suppress the generation of human T^sub H^17 cells. Instead, it has been recently shown that the cytokines IL-1β, IL-6 and IL-23 are capable of driving IL-17 secretion in short-term CD4^sup +^ T cell lines isolated from human peripheral blood, although the factors required for differentiation of naive human CD4 to T^sub H^17 cells are still unknown. Here we confirm that whereas IL-1β and IL-6 induce IL-17A secretion from human central memory CD4^sup +^ T cells, TGF-β and IL-21 uniquely promote the differentiation of human naive CD4^sup +^ T cells into T^sub H^17 cells accompanied by expression of the transcription factor RORC2. These data will allow the investigation of this new population of T^sub H^17 cells in human inflammatory disease. [PUBLICATION ABSTRACT]

Research showing that risk for schizophrenia, bipolar disorder with psychosis, and other psychosis-spectrum diagnoses in adulthood is multidetermined has underscored the necessity of studying the additive and interactive factors in childhood that precede and predict future disorders. In this study, risk for the development of psychosis-spectrum disorders was examined in a 2-generation, 30-year prospective longitudinal study of 3,905 urban families against a sociocultural backdrop of changing economic and social conditions. Peer nominations of aggression, withdrawal, and likeability and national census information on neighborhood-level socioeconomic disadvantage in childhood, as well as changes in neighborhood socioeconomic conditions over the lifespan, were examined as predictors of diagnoses of schizophrenia, bipolar disorder, and other psychosis-spectrum disorders in adulthood relative to developing only nonpsychotic disorders or no psychiatric disorders. Individuals who were both highly aggressive and highly withdrawn were at greater risk for other psychosis-spectrum diagnoses when they experienced greater neighborhood disadvantage in childhood or worsening neighborhood conditions over maturation. Males who were highly aggressive but low on withdrawal were at greater risk for schizophrenia diagnoses. Childhood neighborhood disadvantage predicted both schizophrenia and bipolar diagnoses, regardless of childhood social behavior. Results provided strong support for multiple-domain models of psychopathology, and suggest that universal preventive interventions and social policies aimed at improving neighborhood conditions may be particularly important for decreasing the prevalence of psychosis-spectrum diagnoses in the future.