The EU Center of Excellence for Exascale in Solid Earth (ChEESE): Implementation, results, and roadmap for the second phase

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Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma

BACKGROUND: Approximately 75% of objective responses to anti–programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown. METHODS: We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti–PD-1 therapy (pembrolizumab) followed by disease progression months to years later. RESULTS: Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor–associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I. CONCLUSIONS: In this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI <18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For schoolaged children and adolescents, we report thinness (BMI <2 SD below the median of the WHO growth reference) and obesity (BMI >2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit

Role of PAK4 in immune cell exclusion and resistance to PD-1 blockade immunotherapy

Immune checkpoint blockade therapies constitute one of the major advances in cancer treatment. Despite the long-lasting responses observed in a wide range of tumor types, the majority of patients do not respond or relapse shortly after. In order to increase response rates, we need to better predict patients that would benefit from the treatment as well as identify resistance mechanisms to find novel treatment strategies. However, the interplay between the immune system, the cancer cells and the tumor microenvironment is complex and dynamic, rendering the understanding of resistant mechanisms particularly challenging. Lack of immune cell infiltration constitutes one of the main mechanisms of primary resistance to checkpoint blockade. The absence of T cells on the tumor margin leaves the therapeutic targeting of immune checkpoints ineffective. Interestingly, cancer cell-intrinsic mechanisms could actively participate in the process of immune evasion and importantly, could be pharmacologically targeted to reverse immune exclusion. The finding of actionable molecules that increases T cell infiltration in the tumor could be used in combination with PD-1 blockade, in order to reverse adaptive immune resistance. Here, we characterized the tumors of melanoma patients treated with PD-1 blockade. Our analyses further validated lack of immune cell infiltration as one mechanism of resistance. Importantly, we identified PAK4 as a novel and actionable target that is enriched in biopsies with poor immune infiltration and lack of response to PD-1 blockade. We show how genetically and pharmacologically that inhibition of PAK4 increases immune cell infiltration and improves checkpoint blockade therapy in several in vivo mouse models. We further characterized the impact of inhibiting PAK4 expression. The transcriptomic profiles of PAK4 KO tumors revealed the profound effect that has on the tumor microenvironment, particularly in the genes related to the extracellular matrix and blood vessel formation. This work serves as an example of how direct changes in cancer cells impact the tumor microenvironment and influence the anti-tumor immune response. Importantly, this work also provides the scientific rationale for a novel treatment strategy to combine PAK4 inhibitor with checkpoint blockade

SnapShot: Immune Checkpoint Inhibitors.

Immunotherapy has changed the landscape of cancer treatment. Checkpoint blockade therapies unleash breaks in the immune system and induce long-lasting responses. However, a significant number of patients do not respond (innate resistance), and a subset progress after responding (acquired resistance). A better understanding of the molecular mechanisms underlying checkpoint blockade therapies will facilitate the design of novel strategies to treat and prevent resistance. To view this SnapShot, open or download the PDF

The Effect of <i>Opuntia ficus</i> Mucilage Pectin and <i>Citrus aurantium</i> Extract Added to a Food Matrix on the Gut Microbiota of Lean Humans and Humans with Obesity

Experimental studies have provided evidence that physicochemical interactions in the food matrix can modify the biologically beneficial effects of bioactive compounds, including their effect on gut microbiota. This work aimed to evaluate the effect of a food gel matrix with Opuntia ficus cladodes mucilage pectin and Citrus Aurantium extract on the growth of four beneficial gut bacteria obtained from the fecal microbiota of people who are lean or who have obesity after digestion in the upper digestive system. To accomplish this, a base formulation of Opuntia ficus cladodes mucilage with or without C. aurantium extract was submitted to an ex vivo fecal fermentation in an automatic and robotic intestinal system. The changes in the intestinal microbiota were determined by means of plate culture and 16S sequencing, while short-chain fatty acids (SCFA) produced in the colon were determined via gas chromatography. In the presence of the extract in formulation, greater growth of Bifidobacterium spp. (+1.6 Log10 Colonic Forming Unit, UFC) and Lactobacillus spp. (+2 Log10 UFC) in the microbiota of lean people was observed. Only the growth in Salmonella spp. (−1 Log10 UFC) from both microbiota was affected in the presence of the extract, which decreased in the ascending colon. SCFA was mainly produced by the microbiota of people who were lean rather than those who had obesity in the presence of the extract, particularly in the ascending colon. The effect of sour orange extract seems to depend on the origin of the microbiota, whether in people who have obesity (25 mM/L) or are lean (39 mM/L)

IL-32γ potentiates tumor immunity in melanoma.

Myeloid cells orchestrate the antitumor immune response and influence the efficacy of immune checkpoint blockade (ICB) therapies. We and others have previously shown that IL-32 mediates DC differentiation and macrophage activation. Here, we demonstrate that IL-32 expression in human melanoma positively correlates with overall survival, response to ICB, and an immune-inflamed tumor microenvironment (TME) enriched in mature DC, M1 macrophages, and CD8+ T cells. Treatment of B16F10 murine melanomas with IL-32 increased the frequencies of activated, tumor-specific CD8+ T cells, leading to the induction of systemic tumor immunity. Our mechanistic in vivo studies revealed a potentially novel role of IL-32 in activating intratumoral DC and macrophages to act in concert to prime CD8+ T cells and recruit them into the TME through CCL5. Thereby, IL-32 treatment reduced tumor growth and rendered ICB-resistant B16F10 tumors responsive to anti-PD-1 therapy without toxicity. Furthermore, increased baseline IL-32 gene expression was associated with response to nivolumab and pembrolizumab in 2 independent cohorts of patients with melanoma, implying that IL-32 is a predictive biomarker for anti-PD-1 therapy. Collectively, this study suggests IL-32 as a potent adjuvant in immunotherapy to enhance the efficacy of ICB in patients with non-T cell-inflamed TME