Biology subjects

Zitvogel, L.

Publications and source records attributed to Zitvogel, L..

3 recordsLinked to original sources

bioRxiv2026

Glycometabolic, inflammatory and exocrine plasma proteins predict cancer in individuals with cardiovascular disease

Cancer development is preceded by systemic immune, metabolic and tissue perturbation. We asked whether a minimal circulating-protein signature anticipates incident cancer in patients with atheromatous cardiovascular disease (ACVD) exposed to tobacco. Discovery used a nested case-control set drawn from the longitudinal FLEMENGHO cohort (n=156; 38 incident lung cancers). Multi-omic profiling returned a two-step classifier: four proteins, smoking status, personal cancer history. Preprocessing constants, classifiers and both thresholds were fixed before transfer to PREVALUNG (n=397; 58 incident cancers, 26 of them lung). There, low O-GlcNAcase (OGA) with low interleukin-6 (IL-6) defined a very-low-risk stratum holding 1 of 58 cancers (sensitivity 98.3%, negative predictive value 98.8%); low chymotrypsin C (CTRC) with high beta microseminoprotein (MSMB) defined a high-risk stratum in which 15 of 28 participants developed cancer. No additional omic feature (metabolomic, immunophenotypic, clonal-haematopoietic or metagenomic) was retained as a reproducible improvement to the classifier under our selection framework. Discrimination was greater for cancers diagnosed more than 12 months after sampling than for near-term cancers (AUC 0.766, 95% CI 0.671-0.857, versus 0.589, 0.485-0.692), arguing against performance being driven principally by occult disease. These estimates are conditional on the cancer frequency of this population. They require prospective confirmation before any imaging schedule is changed.

cancer biology↗

bioRxiv2023

Tumor sialylation is a barrier against CD8 T cell-mediated anti-tumor responses and anti-PD-1 resistance in breast cancer

Breast cancer is the most common cancer among women. However, the use of immune checkpoint inhibitors, that have revolutionized treatment of multiple cancers, unfortunately remain largely ineffective in most breast cancer patients. Here, we report the most comprehensive glycoproteome map in breast tumor cells, pointing to a key role of sialic acid modifications in mammary cancer. Genetic and pharmacologic inhibition of sialylation repolarizes the tumor microenvironment, leading to a reduction in myeloid-derived suppressor cells and a significant increase in Tcf7+ memory and CD8+ effector T cells. Mechanistically, sialylation controls cell surface expression of MHC class I and PD-1-ligand on the tumor cells. Functionally, in vivo interference with sialylation on breast cancer cells licenses CD8+ T cells to effectively kill the tumors. In multiple immunotherapy-resistant breast tumor models, we also show that the abrogation of sialylation sensitizes to anti-PD-1 immune checkpoint therapy. We further demonstrate that hyper-sialylation occurs in over half of human breast cancers tested and correlates with poor T cell infiltration. Our results establish sialylation as a central immunoregulator in breast cancer, orchestrating multiple pathways of immune evasion. Targeting tumor sialylation licenses immunologically inert mammary tumors to be efficiently eliminated by anti-cancer immunity and sensitizes to immune checkpoint therapy.

cancer biology↗

bioRxiv2021

Langerhans islets induce anti-tumor immunity at the expense of glycemic control and predict chemotherapy response in pancreatic cancer

Induction of anti-tumor immunity in pancreatic ductal adenocarcinoma (PDA) is an unresolved challenge. Systematic investigation of the microenvironment of primary pancreatic tumors revealed a role of endocrine Langerhans islets in the coordination of immune activation. We found that intratumoral {beta}-cells, regulated via STAT3, secrete C-C motif chemokine ligand 27 (CCL27) and thereby promote a TH1 phenotype in the microenvironment resulting in an enhanced T cell infiltration and prolonged patient survival. The local effect can be abrogated in a patient-based human explant model by inhibition of the CCL27 receptor CCR10. This defense mechanism is paralleled by an impaired metabolic function of Langerhans islets with reduced insulin levels resulting in a dysregulation of glycemic control in patients. Based on these findings, screening of PDA cases (n= 2264) led to the identification of type 2 diabetes mellitus (T2DM) and extractable glycated haemoglobin (HbA1c) levels as response markers for neoadjuvant chemotherapy with fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX). Collectively these data provide insights into the interconnection of T2DM and PDA, and link declining glycemic control to therapeutic efficacy, which can be utilized as a tool for clinical decision-making and improve patient management.

cancer biology↗