Researchers
Fabio Grassi – Group Leader
Tanja Rezzonico-Jost – Staff Scientist
Gaia Salina – Student

Status: in progress

Overview

Secretory immunoglobulin A (SIgA) interaction with commensal bacteria conditions microbiota composition and function. Bacteria-derived adenosine triphosphate (ATP) limits T follicular helper (Tfh) cell activity in the gut associated lymphoid tissue (GALT) via the ionotropic P2X7 receptor (P2X7R) and thereby SIgA generation. Administration of the ATP-degrading enzyme apyrase results in Tfh cells expansion and amplification of the SIgA repertoire. The enhanced breadth of SIgA in mice treated with apyrase influences the topographical distribution of bacteria and expression of genes involved in metabolic versus immune functions in the intestinal epithelium. SIgA-mediated conditioning of bacteria and enterocyte function is reflected by differences in nutrient absorption. Apyrase-induced SIgA improves intestinal homeostasis and attenuates barrier impairment and susceptibility to infection by enteric pathogens in antibiotic-induced dysbiosis. Therefore, we leverage amplification of SIgA by apyrase to restore intestinal fitness in various dysbiotic conditions.

Researchers
Fabio Grassi – Group Leader
Benedetta De Ponti Conti – Student
Elena Carelli – Student
Rebecca Marino – Student

Status: in progress

Overview

Cancer immunotherapy with checkpoint inhibitors (CPIs) increases antitumor immunity by blocking plasma membrane molecules, which suppress T cell anti-tumor activity. The therapeutic efficacy of these biologics is conditioned by the composition of the intestinal microbiota. Therefore, manipulating the microbiota may positively affect cancer immunotherapy outcome. In fact, several conditions of dysbiosis were shown to affect the therapeutic efficacy of CPIs. We aim at enhancing the anti-tumor immune response during cancer immunotherapy by adapting the gut microbiota via secretory IgA (SIgA). Amplification of SIgA repertoire by apyrase administration results in intestine mediated invigoration of the anti-tumor cytotoxic response against solid tumors. We are dissecting the molecular pathways involved in this response and the possibility to convert “cold” tumors into CPIs responsive tumors.

Overview

T cell dependent secretory IgA (SIgA) generated in the Peyer’s patches (PPs) of the small intestine shapes a broadly diverse microbiota that is crucial for host physiology. The mutualistic co-evolution of host and microbes led to the relative tolerance of host’s immune system towards commensal microorganisms. The adenosine triphosphate (ATP)-gated ionotropic P2X7 receptor limits T follicular helper (Tfh) cells expansion and germinal center (GC) reaction in the PPs. We have shown that transient depletion of intestinal ATP can dramatically improve high-affinity IgA response against both live and inactivated oral vaccines. Ectopic expression of Shigella flexneri periplasmic ATP-diphosphohydrolase (apyrase) abolishes ATP release by bacteria and improves the specific IgA response against live oral vaccines. Antibody responses primed in the absence of intestinal extracellular ATP (eATP) also provide superior protection from enteropathogenic infection. We are applying this knowledge to the generation of a new class of mucosal vaccines with enhanced efficacy.

Although P2rx7 has been proposed as a type 1 diabetes (T1D) susceptibility gene in non-obese diabetic (NOD) mice, its potential pathogenic role has not been directly determined. To test this possibility we investigated P2rx7 expression in CD4⁺CD62L^highCD44^low naive and CD4⁺CD62L^lowCD44^high effector from pancreatic lymph nodes of healthy, prediabetic and overtly diabetic NOD mice. P2rx7 expression significantly increases in CD4⁺ T effector cells of prediabetic NOD mice but dramatically decreases in NOD mice with overt disease. Since P2rx7 is silenced by cognate antigen stimulation these observations underscore the relevance of pancreatic epitope spreading in the development of T1D in NOD mice. Downregulation of P2rx7 would render effector T cells resistant to pyroptosis induction by extracellular ATP generated by inflammatory tissue damage, thereby propagating and sustaining tissue destruction. The role of P2X7 activity in limiting the T cell diabetogenic potential was supported by T1D induction with low-dose of streptozotocin in P2rx7 knock-out mice, which developed a significantly more severe disease than the wild-type counterpart.

Overview

Peculiar features of the tumor microenvironment condition the function of infiltrating immune system cells and eventually protect the malignant tissue from eradication. Extracellular adenosine triphosphate (eATP) is a signaling molecule, which variably affects directly or after hydrolysis to adenosine, all cells of the immune system. Whereas eATP is virtually absent in the interstitium of normal tissues, it can be present in the hundreds micromolar range in tumors, a concentration compatible with activation of the ATP-gated ionotropic P2X7 receptor. We found that P2X7 activity in tumor-infiltrating effector T cells limits cell proliferation and tumor suppression. In these cells, deletion of P2rx7, encoding for P2X7, promotes a transcriptional signature that correlates with enhanced cytotoxic T cell response in human solid tumors. Therefore, we address the role of the eATP/P2X7 axis in conditioning the cytotoxic activity of tumor-infiltrating lymphocytes.