MTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function.

Antigenic stimulation promotes T cell metabolic reprogramming to meet increased biosynthetic, bioenergetic, and signaling demands. We show that the one-carbon (1C) metabolism enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) regulates de novo purine synthesis and signaling in activated T cells to promote proliferation and inflammatory cytokine production. In pathogenic T helper-17 (Th17) cells, MTHFD2 prevented aberrant upregulation of the transcription factor FoxP3 along with inappropriate gain of suppressive capacity. MTHFD2 deficiency also promoted regulatory T (Treg) cell differentiation. Mechanistically, MTHFD2 inhibition led to depletion of purine pools, accumulation of purine biosynthetic intermediates, and decreased nutrient sensor mTORC1 signaling. MTHFD2 was also critical to regulate DNA and histone methylation in Th17 cells. Importantly, MTHFD2 deficiency reduced disease severity in multiple in vivo inflammatory disease models. MTHFD2 is thus a metabolic checkpoint to integrate purine metabolism with pathogenic effector cell signaling and is a potential therapeutic target within 1C metabolism pathways.

Hematologic Complications of Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors have improved outcomes for patients with numerous hematological and solid cancers. Hematologic toxicities have been described, but the spectrum, timing, and clinical presentation of these complications are not well understood. We used the World Health Organization's pharmacovigilance database of individual-case-safety-reports (ICSRs) of adverse drug reactions, VigiBase, to identify cases of hematologic toxicities complicating immune checkpoint inhibitor therapy. We identified 168 ICSRs of immune thrombocytopenic purpura (ITP), hemolytic anemia (HA), hemophagocytic lymphohistiocytosis, aplastic anemia, and pure red cell aplasia in 164 ICSRs. ITP (n = 68) and HA (n = 57) were the most common of these toxicities and occurred concomitantly in four patients. These events occurred early on treatment (median 40 days) and were associated with fatal outcome in 12% of cases. Ipilimumab-based therapy (monotherapy or combination with anti-programmed death-1 [PD-1]) was associated with earlier onset (median 23 vs. 47.5 days, p = .006) than anti-PD-1/programmed death ligand-1 monotherapy. Reporting of hematologic toxicities has increased over the past 2 years (98 cases between January 2017 and March 2018 vs. 70 cases before 2017), possibly because of increased use of checkpoint inhibitors and improved recognition of toxicities. Future studies should evaluate incidence of hematologic toxicities, elucidate risk factors, and determine the most effective treatment algorithms. KEY POINTS: Immune-mediated hematologic toxicities are a potential side effect of immune checkpoint inhibitors (ICIs).Providers should monitor complete blood counts during treatment with ICIs.Corticosteroids are the mainstay of treatment for immune-mediated hematologic toxicities.Further research is needed to define patient-specific risk factors and optimal management strategies for hematologic toxicities.

Painful blue fingers.

The patient's history of lupus held the clue to the diagnosis.

Living with Systemic Sclerosis: A Patient and Physician Perspective.

The fears associated with being diagnosed with a disease unfamiliar to many, systemic sclerosis, is described by a patient living with systemic sclerosis. The patient, a coauthor, also describes the challenges of being a young person diagnosed with a chronic and, at times, debilitating disease. Despite initially being told that she had 6 months to live, she has embraced life and has become a fierce advocate for others living with systemic sclerosis. The physician perspective is provided by two rheumatologists who specialize in systemic sclerosis and work at a scleroderma center of excellence. This section details the current challenges in diagnosing systemic sclerosis early and the dangers of a delayed diagnosis. It also reviews the importance of multi-disciplinary specialty centers in the care of patients with systemic sclerosis as well as empowering patients through education.

Elevated transferrin receptor impairs T cell metabolism and function in systemic lupus erythematosus.

T cells in systemic lupus erythematosus (SLE) exhibit multiple metabolic abnormalities. Excess iron can impair mitochondria and may contribute to SLE. To gain insights into this potential role of iron in SLE, we performed a CRISPR screen of iron handling genes on T cells. Transferrin receptor (CD71) was identified as differentially critical for TH1 and inhibitory for induced regulatory T cells (iTregs). Activated T cells induced CD71 and iron uptake, which was exaggerated in SLE-prone T cells. Cell surface CD71 was enhanced in SLE-prone T cells by increased endosomal recycling. Blocking CD71 reduced intracellular iron and mTORC1 signaling, which inhibited TH1 and TH17 cells yet enhanced iTregs. In vivo treatment reduced kidney pathology and increased CD4 T cell production of IL-10 in SLE-prone mice. Disease severity correlated with CD71 expression on TH17 cells from patients with SLE, and blocking CD71 in vitro enhanced IL-10 secretion. T cell iron uptake via CD71 thus contributes to T cell dysfunction and can be targeted to limit SLE-associated pathology.

Impact of body composition on outcomes from anti-PD1 +/- anti-CTLA-4 treatment in melanoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed treatment for melanoma, but identifying reliable biomarkers of response and effective modifiable lifestyle factors has been challenging. Obesity has been correlated with improved responses to ICI, although the association of body composition measures (muscle, fat, etc) with outcomes remains unknown. METHODS: We performed body composition analysis using Slice-o-matic software on pretreatment CT scans to quantify skeletal muscle index (SMI=skeletal muscle area/height2), skeletal muscle density (SMD), skeletal muscle gauge (SMG=SMI × SMD), and total adipose tissue index (TATI=subcutaneous adipose tissue area + visceral adipose tissue area/height2) of each patient at the third lumbar vertebrae. We then correlated these measures to response, progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: Among 287 patients treated with ICI, body mass index was not associated with clinical benefit or toxicity. In univariable analyses, patients with sarcopenic obesity had inferior PFS (HR 1.4, p=0.04). On multivariable analyses, high TATI was associated with inferior PFS (HR 1.7, p=0.04), which was particularly strong in women (HR 2.1, p=0.03). Patients with intermediate TATI and high SMG had the best outcomes, whereas those with low SMG/high TATI had inferior PFS and OS (p=0.02 for both PFS and OS). CONCLUSIONS: Body composition analysis identified several features that correlated with improved clinical outcomes, although the associations were modest. As with other studies, we identified sex-specific associations that warrant further study.

Survivorship in immune therapy: Assessing toxicities, body composition and health-related quality of life among long-term survivors treated with antibodies to programmed death-1 receptor and its ligand.

AIM: Antibodies to programmed death-1 receptor and its ligand (anti-PD-1/PD-L1) produce durable responses in many cancers. However, the long-term effects of anti-PD-1/PD-L1 blockade are not well defined. We identified the toxicities, health outcomes and health-related quality of life (HRQoL) amongst long-term survivors treated with anti-PD-1/PD-L1. METHODS: We assessed 217 patients who received anti-PD-1/PD-L1 for melanoma, renal cell carcinoma or non-small-cell lung carcinoma between 2009 and 2017, with survival greater than two years after treatment. Patient and tumour characteristics, immune-related adverse events (irAEs), cardiometabolic parameters (glucose, blood pressure, body mass index [BMI]), body composition (using automated body composition analyser, computed tomography and Slice-o-matic software) and HRQoL outcomes were tracked. RESULTS: Among the included patients, most were men (70.3%) and at anti-PD-1/PD-L1 initiation had an average age of 61.0 years and median BMI of 28.5. Median overall survival was not reached; 33 (15.2%) died during the follow-up primarily from progressive cancer (n = 28). At the last follow-up, most patients' Eastern Cooperative Oncology Group performance status was 0 (38%) or 1 (41%). There was no difference in blood pressure, glucose or BMI from baseline to two years after treatment initiation. Body composition showed increased adiposity (p = 0.05), skeletal muscle mass (p = 0.03) and skeletal muscle gauge (p = 0.04). We observed chronic irAEs at the last follow-up including hypothyroidism (10.6%), arthritis (3.2%), adrenal insufficiency (3.2%) and neuropathy (2.8%). New diagnoses of type 2 diabetes (6.5%) and hypertension (6.0%) were observed, with uncertain relationship to anti-PD-1/PD-L1. Patient-reported outcomes compared favourably with cancer and general populations, although younger age (p = 0.003) and need for subsequent therapy (p = 0.03) were associated with worse HRQoL outcomes. CONCLUSION: Durable responses to anti-PD-1/PD-L1 therapy and favourable HRQoL outcomes are encouraging. Chronic events may be more common than previously thought although no clear chronic adverse cardiometabolic effects were observed.

Pre- to post-diagnosis weight change and associations with physical functional limitations in breast cancer survivors.

PURPOSE: We investigated pre- to post-diagnosis weight change and functional limitations in a cohort of breast cancer survivors. METHODS: A cohort of 1,841 early-stage breast cancer survivors provided information on pre- and post-diagnosis weight and physical function on average 2 years post-diagnosis. The mean number of limitations for each BMI category and each weight change category were compared using the Wilcoxon test. Cross-sectional associations between weight change, from 1 year prior to diagnosis to 2 years post-diagnosis, and functional limitations were determined using logistic regression. RESULTS: Women with BMI ≥ 30 kg/m(2) had significantly higher physical limitations compared to women with BMI < 25 kg/m(2) (2.06 vs 0.96 for moderate/severe limitations, 3.92 vs 3.27 for mild limitations, 1.31 vs 0.47 for lower body limitations, and 0.76 vs 0.49 for all other limitations; P < 0.0001). Women who reported a large weight gain (≥10% of pre-diagnosis weight) were more likely to report any limitation (OR = 1.79; 95% confidence interval (CI) = 1.23-2.61), a moderate/severe limitation (OR = 2.30; 95% CI = 1.75-3.02), and a lower body limitation (OR = 2.05; 95% CI = 1.53-2.76) compared to women who maintained weight within 5% of pre-diagnosis weight. However, associations between weight loss and functional limitations depended on pre-diagnosis BMI and comorbidity status. Among women without comorbidity, large weight loss (≥10% of pre-diagnosis weight) in normal-weight women was associated with higher risk of functional limitations, whereas among overweight/obese women, large weight loss appeared to be associated with a lower risk of limitations. Among women with comorbidity, moderate weight loss in overweight/obese women was associated with a higher risk of a moderate/severe physical limitation. CONCLUSIONS: Large weight gain was associated with a higher risk of physical functional limitations, but associations between weight loss and functional limitations may depend on initial BMI and comorbidity status. IMPLICATIONS FOR CANCER SURVIVORS: In this study we found that both weight loss and weight gain among breast cancer survivors were associated with a higher risk of physical functional limitations. Weight maintenance, therefore, may be an important factor in preventing and/or reducing the risk of functional decline in breast cancer survivors.