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The ability of CD8 + T cells to infiltrate solid tumors and reach cancer cells is associated with improved patient survival and responses to immunotherapy. Thus, identifying the factors controlling T cell migration in tumors is critical, so that strategies to intervene on these targets can be developed. Although interstitial motility is a highly energy-demanding process, the metabolic requirements of CD8 + T cells migrating in a 3D environment remain unclear. Here, we demonstrate that the tricarboxylic acid (TCA) cycle is the main metabolic pathway sustaining human CD8 + T cell motility in 3D collagen gels and tumor slices while glycolysis plays a more minor role. Using pharmacological and genetic approaches, we report that CD8 + T cell migration depends on the mitochondrial oxidation of glucose and glutamine, but not fatty acids, and both ATP and ROS produced by mitochondria are required for T cells to migrate. Pharmacological interventions to increase mitochondrial activity improve CD8 + T cell intratumoral migration and CAR T cell recruitment into tumor islets leading to better control of tumor growth in human xenograft models. Our study highlights the rationale of targeting mitochondrial metabolism to enhance the migration and antitumor efficacy of CAR T cells in treating solid tumors., (© 2024. The Author(s).)

Background: Few epidemiological data are available on surgically treated Caucasian patients with non-small-cell lung cancers (NSCLCs) harboring epidermal growth factor receptor ( EGFR ) mutations. The main objective of this study was to describe, in the real-world setting, these patients' incidence, clinical, and tumoral characteristics., Methods: The participating centers included all consecutive localized non-squamous NSCLC patients undergoing surgery between January 2018 and December 2019 in France. EGFR status was determined retrospectively when not available before surgery., Results: The study includes 1391 no squamous NSCLC patients from 16 centers; EGFR status was determined before surgery in 692 (49.7%) of the cases and conducted as part of the study for 699 (50.3%); 171 (12.3%) were EGFR mutated; median age: 70 (range: 36-88) years; female: 59.6%; never smokers: 75.7%; non-squamous histology 97.7%, programmed death ligand-1 expression 0%/1-49%/⩾50 in 60.5%/25.7%/13.8%, respectively. Surgery was predominantly lobectomy (81%) or segmentectomy (14.9%), with systematic lymph node dissection in 95.9%. Resection completeness was R0 for 97%. Post-surgery staging was as follows: IA: 52%, IB: 16%, IIA: 4%, IIB: 10%, IIIA: 16%, and IIIB: 0.05%; EGFR mutation exon was Del19/exon 21 ( L858R )/20/18 in 37.4%/36.8%/14%, and 6.4% of cases, respectively; 31 (18%) patients received adjuvant treatment (chemotherapy: 93%, EGFR tyrosine kinase inhibitor: 0%, radiotherapy: 20%). After a median follow-up of 31 (95% confidence interval: 29.6-33.1) months, 45 (26%) patients relapsed: 11/45 (24%) locally and 34 (76%) with metastatic progression. Median disease-free survival (DFS) and overall survival were not reached and 3-year DFS was 60%., Conclusion: This real-world analysis provides the incidence and outcomes of resected EGFR -mutated NSCLCs in a European patient cohort., Competing Interests: J-BA: In the last 5 years, J-BA has received honoraria for attending scientific meetings, speaking, organizing research, or consulting, from Boehringer Ingelheim, Hoffman-Roche, Takeda, BMS, MSD, Astra Zeneca, Amgen, and Pfizer., (© The Author(s), 2024.)

EBV-positive inflammatory follicular dendritic cell sarcoma (EBV+ inflammatory FDCS) is a rare neoplasm almost exclusively located in the spleen or liver. It is characterized by a proliferation of EBV-positive spindle-shaped cells bearing follicular dendritic cell markers, associated with an abundant lymphoplasmacytic infiltrate. EBV+ inflammatory FDCS is often asymptomatic or responsible for mild symptoms. It usually displays an indolent course and its prognosis is excellent after tumor removal, although relapsing and metastatic forms exist. Herein, we describe an aggressive form of splenic EBV+ inflammatory FDCS in a 79-year-old woman presenting with abdominal pain, deterioration of general health status, major inflammatory syndrome, and symptomatic hypercalcemia. A splenectomy was performed leading to a rapid improvement in her clinical condition and normalization of laboratory abnormalities. Unfortunately, her symptoms and laboratory abnormalities reappeared 4 months later. Computed tomography showed a mass in the splenectomy site and multiple liver and peritoneal nodules. Further analyses were performed on tumor tissue and showed positive phospho-ERK staining of tumoral cells indicating activation of MAPK pathway. Inactivating mutations were found on CDKN2A and NF1 genes. Subsequently, the patient's condition deteriorated rapidly. Since interleukin-6 levels were dramatically increased, tocilizumab was used but only had a transient effect on the patient's symptoms and inflammatory syndrome. Antitumor agent gemcitabine was initiated but her clinical condition continued to deteriorate and the patient died 2 weeks later. The management of aggressive forms of EBV+ inflammatory FDCS remains challenging. However, since these tumors seem to display genetic alterations, better characterization could lead to molecular targeted therapies., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background & Aims: Sarcopenia has long been associated with higher toxicity induced by anti-cancer treatments and shorter survival in patients with solid tumors. The creatinine-to-cystatin ratio (CC ratio, serum creatinine/cystatin C × 100) and the sarcopenia index (SI, serum creatinine × cystatin C (CysC)-based glomerular filtration rate (eGFR CysC )) are have been reported to be correlated with skeletal muscle mass. The aim of this study is to assess primarily whether the CC ratio and the SI could predict mortality in metastatic non-small cell lung cancer (NSCLC) patients treated with PD-1 inhibitors, and secondarily their impact on severe immune-related adverse effects (irAEs)., Methods: From the prospective CERTIM cohort, we analyzed retrospectively stage IV NSCLC patients, who received PD-1 inhibitors between June 2015 and November 2020 in Cochin Hospital (Paris, France). We assessed sarcopenia measuring skeletal muscle area (SMA) by computed tomography and handgrip strength (HGS) by a hand dynamometer., Results: In total, 200 patients were analyzed. The CC ratio and the IS were significantly correlated with SMA and HGS: r CC/SMA  = 0.360, r SI/SMA  = 0.407, r CC/HGS  = 0.331, r SI/HGS  = 0.370. In multivariate analysis of overall survival, a lower CC ratio (HR 1.73, P = 0.033) and a lower SI (HR 1.89, P = 0.019) were independent predictors of poor prognosis. In univariate analysis of severe irAEs, CC ratio (OR 1.01, P = 0.628) and SI (OR 0.99, P = 0.595) were not associated with a higher risk of severe irAEs., Conclusions: In metastatic NSCLC patients treated with PD-1 inhibitors, a lower CC ratio and a lower SI are independent predictors of mortality. However, they are not associated with severe irAEs., Competing Interests: Conflicts of interest Jérôme Alexandre received honoraria from Astra Zeneca, MSD, GSK, Eisai, Clovis and Novartis. Marco Alifano received consulting fees from Roche and Astra Zaneca, honoraria from Roche, Astra Zaneca and AMGEN and travel accommodation from Medtronic. Jennifer Arrondeau received honoraria from BMS and Astra Zaneca and meeting accommodation from Pfizer. Pascaline Boudou-Rouquette received personal fees from Takeda, Pharmama and IPSEN. Diane Damotte received a research grant from Astra Zaneca. François Goldwasser served on advisory board for Fresenius Kabi and Nutricia and received research grant from Baxter International Inc, USA. Olivier Huillard received honoraria from Bristol-Myers Squibb, Astellas, IPSEN, MSD, Pfizer, Janssen, Astra Zaneca, Bayer and AAA Novartis and travel accommodation from IPSEN and AAA Novartis. Elisabeth Ashton, Laure Hirsch, Anne Jouinot, Audrey Lupo-Mansuet, Guillaume Ulmann and Marie Wislez have no conflict of interest to declare., (Copyright © 2023 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)