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B7-H4 functions as an immune checkpoint in the tumor microenvironment (TME). However, the post-translational modification (PTM) of B7-H4 and its translational potential in cancer remains incompletely understood. We find that ZDHHC3, a zinc finger DHHC-type palmitoyltransferase, palmitoylates B7-H4 at Cys130 in breast cancer cells, preventing its lysosomal degradation and sustaining B7-H4-mediated immunosuppression. Knockdown of ZDHHC3 in tumors results in robust anti-tumor immunity and reduces tumor progression in murine models. Moreover, abemaciclib, a CDK4/6 inhibitor, primes lysosome activation and promotes lysosomal degradation of B7-H4 independently of the tumor cell cycle. Treatment with abemaciclib results in T cell activation and mitigates B7-H4-mediated immune suppression via inducing B7-H4 degradation in preclinical tumor models. Thus, B7-H4 palmitoylation is an important PTM controlling B7-H4 protein stability and abemaciclib may be repurposed to promote B7-H4 degradation, thereby treating patients with B7-H4 expressing tumors. The immune checkpoint B7-H4 is regulated through post-translational modifications. Here, the authors identify that in breast cancer cells ZDHHC3-catalyzed B7-H4 palmitoylation prevents its lysosomal degradation and maintains immune suppression, which can be targeted by Abemaciclib to enhance lysosome activation independently of CDK4/6 inhibition.

Global change is affecting native species and communities through multiple anthropogenic drivers which likely interact, complicating our ability to predict the net effects of global change. In the Pacific Northwest region (USA), Cytisus scoparius (L.) Link (Scotch broom) invasion has dramatically altered many ecosystems, including postharvest timber lands. Simultaneously, the intensity of summer drought conditions associated with climate change is making successful reforestation increasingly difficult. We investigated how Douglas‐fir (Pseudotsuga menziesii (Mirb.) Franco var. menziesii) responds to the multiple stressors of drought and Cytisus invasion. We further evaluated whether the soil microbial community, including mycorrhizal fungi, ameliorates or exacerbates Douglas‐fir's response to drought and Cytisus competition. Drought and the presence of the invader both increased stress (measured by chlorophyll fluorescence) and decreased survival of Douglas‐fir seedlings, and their combined effects on stress were more than additive. Douglas‐fir grew bigger in live than in sterile soil, but this effect was strongly reduced in the presence of Cytisus; we also found that mycorrhizal colonization was reduced in the presence of the invader. Surprisingly, however, Douglas‐fir survival in live soil was lower than in sterile soil, especially in the presence of Cytisus. Our results suggest that the impact of drought on Douglas‐fir seedlings is likely to be exacerbated by the invasion of Cytisus. Our results further suggest that in a warming climate, the presence of impactful invasive species can affect whether soil microbes have a net positive or negative effect on native plant performance. Our results illustrate the value of studying multiple stressors simultaneously to understand their interactions and combined impacts on native species.

Tumor-associated macrophages (TAMs) affect cancer progression and therapy. Ovarian carcinoma often metastasizes to the peritoneal cavity. Here, we found 2 peritoneal macrophage subsets in mice bearing ID8 ovarian cancer based on T cell immunoglobulin and mucin domain containing 4 (Tim-4) expression. Tim-4+ TAMs were embryonically originated and locally sustained while Tim-4- TAMs were replenished from circulating monocytes. Tim-4+ TAMs, but not Tim-4- TAMs, promoted tumor growth in vivo. Relative to Tim-4- TAMs, Tim-4+ TAMs manifested high oxidative phosphorylation and adapted mitophagy to alleviate oxidative stress. High levels of arginase-1 in Tim-4+ TAMs contributed to potent mitophagy activities via weakened mTORC1 activation due to low arginine resultant from arginase-1-mediated metabolism. Furthermore, genetic deficiency of autophagy element FAK family-interacting protein of 200 kDa resulted in Tim-4+ TAM loss via ROS-mediated apoptosis and elevated T cell immunity and ID8 tumor inhibition in vivo. Moreover, human ovarian cancer-associated macrophages positive for complement receptor of the immunoglobulin superfamily (CRIg) were transcriptionally, metabolically, and functionally similar to murine Tim-4+ TAMs. Thus, targeting CRIg+ (Tim-4+) TAMs may potentially treat patients with ovarian cancer with peritoneal metastasis.

Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic cells (DC) and other myeloid cells with antigen presenting and cancer cell killing capacities is an attractive but not fully exploited approach. Here, we show that PIKFYVE is a shared gene target of clinically relevant protein kinase inhibitors and high expression of this gene in DCs is associated with poor patient response to immune checkpoint blockade (ICB) therapy. Genetic and pharmacological studies demonstrate that PIKfyve ablation enhances the function of CD11c + cells (predominantly dendritic cells) via selectively altering the non-canonical NF-κB pathway. Both loss of Pikfyve in CD11c + cells and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively regulates the function of CD11c + cells, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies. Myeloid cell subsets are playing important roles in antitumour immunity, and genes affecting their functions are potential targets for immunotherapy. Here authors show that genomic deletion of Pikfyve in CD11c + cells results in tumour growth inhibition via enhanced antigen presentation and priming of antigen-specific CD8 + T cells in a mouse tumor model.

Abnormal epigenetic patterns correlate with effector T cell malfunction in tumours 1 – 4 , but the cause of this link is unknown. Here we show that tumour cells disrupt methionine metabolism in CD8 + T cells, thereby lowering intracellular levels of methionine and the methyl donor S -adenosylmethionine (SAM) and resulting in loss of dimethylation at lysine 79 of histone H3 (H3K79me2). Loss of H3K79me2 led to low expression of STAT5 and impaired T cell immunity. Mechanistically, tumour cells avidly consumed methionine and outcompeted T cells for methionine by expressing high levels of the methionine transporter SLC43A2. Genetic and biochemical inhibition of tumour SLC43A2 restored H3K79me2 in T cells, thereby boosting spontaneous and checkpoint-induced tumour immunity. Moreover, methionine supplementation improved the expression of H3K79me2 and STAT5 in T cells, and this was accompanied by increased T cell immunity in tumour-bearing mice and patients with colon cancer. Clinically, tumour SLC43A2 correlated negatively with T cell histone methylation and functional gene signatures. Our results identify a mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumour microenvironment. Thus, cancer methionine consumption is an immune evasion mechanism, and targeting cancer methionine signalling may provide an immunotherapeutic approach. Expression of the transporter SLC43A2 by tumour cells allows them to outcompete T cells for methionine and thereby disrupt the survival and function of tumour-infiltrating T cells.

Major histocompatibility complex-I (MHC-I) presents tumour antigens to CD8 + T cells and triggers anti-tumour immunity. Humans may have 30,000–60,000 long noncoding RNAs (lncRNAs). However, it remains poorly understood whether lncRNAs affect tumour immunity. Here, we identify a lncRNA, lncRNA inducing MHC-I and immunogenicity of tumour (LIMIT), in humans and mice. We found that IFNγ stimulated LIMIT, LIMIT cis -activated the guanylate-binding protein (GBP) gene cluster and GBPs disrupted the association between HSP90 and heat shock factor-1 (HSF1), thereby resulting in HSF1 activation and transcription of MHC-I machinery, but not PD-L1. RNA-guided CRISPR activation of LIMIT boosted GBPs and MHC-I, and potentiated tumour immunogenicity and checkpoint therapy. Silencing LIMIT , GBPs and/or HSF1 diminished MHC-I, impaired antitumour immunity and blunted immunotherapy efficacy. Clinically, LIMIT, GBP- and HSF1-signalling transcripts and proteins correlated with MHC-I, tumour-infiltrating T cells and checkpoint blockade response in patients with cancer. Together, we demonstrate that LIMIT is a cancer immunogenic lncRNA and the LIMIT–GBP–HSF1 axis may be targetable for cancer immunotherapy. Li et al. identify LIMIT as a lncRNA that modulates MHC-I expression through HSP90 and HSF1, thereby regulating antitumour immune response and the efficacy of immunotherapy.

1. An increasingly recognized impact of plant invaders is the disruption of positive interactions between native plants and their belowground mutualistic mycorrhizal fungi. We reviewed 112 studies from 61 publications that report invader impacts on mycorrhizal fungi. We describe emerging patterns on the frequency of negative, neutral and positive invader effects on mycorrhizal fungal abundance, richness and community composition, and we evaluate how these outcomes vary with invasion age. We also describe the evidence for three mechanisms of disruption: (1) plant-plant competition that alters host quantity or quality (2) changes in soil properties such as nutrient availability and (3) allelopathy. 2. Invaders can disrupt native mutualisms if they are non-mycorrhizal, associate with a different type of mycorrhiza, or associate with different taxa of the same type of mycorrhiza as the native plants. Invaders that enrich soil nutrients can cause declines in mycorrhizal abundance, shifts in fungal community composition, and cause native plants to reduce their dependence on mycorrhizas. Invaders that produce allelopathic compounds cause mycorrhizal abundance to decrease and alter community composition because of variation in the sensitivity of different fungi to toxins. 3. While the evidence for disruption of the mycorrhizal mutualism with invasion is strong, temporal patterns have not yet emerged from the literature. Invasion age was not clearly associated with extent of disruption, and the timing of recovery following invader removal was highly variable. Differences in the biology of native and invasive plants, their interactions with mycorrhizal fungi and the surrounding landscape contributed to this variation. 4. Synthesis. Our systematic review suggests that invaders frequently decrease mycorrhizal abundance and alter fungal community composition while only occasionally affecting fungal species richness. The development of invader impacts, as well as the restoration of native communities after invader removal, are influenced by a suite of plant, fungal and environmental traits that change over time. However, few studies have examined the temporal dynamics of mycorrhizal disruption, and results are variable. Future research should focus on the temporal scale of mutualism disruption while considering plant phylogenetics and demography, fungal functional traits such as spore longevity and dispersal, and soil chemistry.

Both invasive species and their biological control agents face barriers to expansion, which provide opportunities to limit invasions or may enable target invasive species to exist in enemy-free space. A better understanding of the various barriers to the spread of insects introduced to control invasive plants will allow for more targeted release programs and potentially shorter lag times from introduction to management. In the Pacific Northwest of the United States, two seed eating beetles (Exapion fuscirostre and Bruchidius villosus) have been introduced to control the invasive plant Cytisus scoparius. These biological controls are predicted to be effective only at high rates of seed destruction, so any factors that limit their colonization or population sizes may allow C. scoparius populations to grow, leading to ecological and economic harm. In this study, we investigate relative impacts of biological control agents in relation to two barriers to insect movement: urbanization and elevation. We find that the impacts of B. villosus are not different between urban and rural sites, but that relative impacts of both biological control agents decrease with increasing elevation, a pattern consistent across 2 years of measurements. Cytisus scoparius populations experience substantial seed destruction in urban settings, strongly suggesting successful population control. The low seed destruction at high elevation sites could indicate that biological control agents are ineffective there, and that C. scoparius may exist in enemy-reduced space.

Targeting the p53–MDM2 pathway to reactivate tumor p53 is a chemotherapeutic approach. However, the involvement of this pathway in CD8 + T cell-mediated antitumor immunity is unknown. Here, we report that mice with MDM2 deficiency in T cells exhibit accelerated tumor progression and a decrease in tumor-infiltrating CD8 + T cell survival and function. Mechanistically, MDM2 competes with c-Cbl for STAT5 binding, reduces c-Cbl-mediated STAT5 degradation and enhances STAT5 stability in tumor-infiltrating CD8 + T cells. Targeting the p53–MDM2 interaction with a pharmacological agent, APG-115, augmented MDM2 in T cells, thereby stabilizing STAT5, boosting T cell immunity and synergizing with cancer immunotherapy. Unexpectedly, these effects of APG-115 were dependent on p53 and MDM2 in T cells. Clinically, MDM2 abundance correlated with T cell function and interferon-γ signature in patients with cancer. Thus, the p53–MDM2 pathway controls T cell immunity, and targeting this pathway may treat patients with cancer regardless of tumor p53 status. The E3 ubiquitin ligase MDM2 inhibits the tumor suppressor p53 and is an important therapeutic target. Zou and colleagues demonstrate that MDM2 also has a T cell-intrinsic role that supports antitumor responses.

Invasive species may leave behind legacies that persist even after removal, inhibiting subsequent restoration efforts. We examined the soil legacy of Cytisus scoparius, a nitrogen-fixing, putatively allelopathic shrub invading the western US. We tested the hypothesis that allelopathy plays a critical role in the depressive effect of Cytisus on the key native Douglas-fir, both directly on tree growth and indirectly via effects on its ectomycorrhizal fungi (EMF). In a greenhouse factorial experiment, we used activated carbon to inhibit Cytisus-produced allelochemicals and sucrose to reduce elevated nitrogen (N). We found that: (1) Cytisus-invaded soils depressed Douglas-fir growth compared to uninvaded forest soils. The effect of adding Cytisus litter was positive (possibly reflecting an N fertilization effect) only in the presence of activated carbon, providing evidence for a role of allelopathic compounds. Activated carbon did not increase growth in the absence of Cytisus litter. Finally, sucrose addition provided weak support for a nitrogen effect of Cytisus litter. (2) Seedlings grown in Cytisus soils had lower EMF abundance compared to those in uninvaded forest soils. In forest soil from one site, adding Cytisus litter also decreased EMF abundance. Douglas-fir growth increased significantly with EMF across sites and soils suggesting that changes in EMF were linked to tree growth. The fungal taxon Cenococcum geophilum was significantly depressed in Cytisus soils compared to forest soils, while Rhizopogon rogersii abundance was similar across soil types. These results together suggest an overall negative effect of Cytisus on the growth of a dominant native tree and its fungal symbionts. Our study suggests how the role of allelopathy in ecological restoration may play out on two time scales: through immediate, direct impacts on native plants as well as through long-term, persistent impacts mediated by the collapse or transformation of microbial communities.