Biology subjects

Marcovecchio, P.

Publications and source records attributed to Marcovecchio, P..

3 recordsLinked to original sources

bioRxiv2025

Therapeutic Blockade of Type 2 Cytokines and PD1 Unleashes Anti-Tumor Immunity Through Coordinated Reprogramming of Innate and Adaptive Immune Surveillance

BackgroundCheckpoint inhibitors improve survival in patients with several types of tumors. However, resistance to checkpoint inhibitors creates an opportunity for patients to benefit from novel immunotherapies. The type 2 cytokines IL-4, IL-13 and TSLP have been implicated in suppressing anti-tumor immune responses through T and myeloid cells. Our current study tested whether combined therapeutic blockade of IL-4, IL-13 and TSLP improved anti-tumor immunity alone and in combination with PD1 antagonism. MethodsWe used in vitro experiments with primary cells to identify cell types likely to participate in controlling tumors upon IL-4, IL-13, TSLP and PD1 blockade. Therapeutic blockade in the subcutaneous CT26 model tested in vivo tumor growth inhibition and associated immunological changes. Bioinformatic analysis of human tumor bulk RNA sequencing data probed for survival associations with IL-4/IL-13 and TSLP transcriptional responses. ResultsIn vitro, IL-4 suppressed T cell-mediated tumor growth inhibition and reduced monocyte-derived dendritic cell expression of proteins associated with anti-tumor immunity. In vivo, blocking IL-4, IL-13, TSLP and PD1 improved tumor growth inhibition by creating "hotter" tumors. This was associated with repolarization of CD4 and CD8 T cells and shifts in monocyte, conventional type 1 and type 2 (or monocyte-derived) dendritic cell programs. Transcriptional responses to IL-4/IL-13 and TSLP were associated with poor survival outcomes across patients with several types of cancers. ConclusionTherapeutic blockade of IL-4, IL-13 and TSLP may drive immunological tumor growth inhibition in subsets of cancer patients alone and in combination with checkpoint inhibitors. Improved tumor growth inhibition was likely driven through augmented cytotoxic T cell priming in secondary lymphoid organs and improved reactivation by repolarized monocytes and dendritic cells in tumors.

cancer biology↗

bioRxiv2021

Specialized subsets of innate-like T cells and dendritic cells protect from lethal pneumococcal infection in the lung

Innate-like T cells, including invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells and {gamma}{delta} T cells, are present in various barrier tissues, including the lung. They carry out protective responses during infections, but the mechanisms for protection are not completely understood. Here, we investigated their roles during pulmonary infection with Streptococcus pneumoniae. Following infection, innate-like T cells rapidly increased in lung tissue, in part through recruitment, but TCR activation and cytokine production occurred mostly in IL-17-producing NKT17 and {gamma}{delta} T cells. NKT17 cells were preferentially located outside the vasculature prior to infection, as were CD103+ dendritic cells (cDC1), which were important both for antigen presentation to NKT17 cells and {gamma}{delta} T cell activation. Whereas IL-17A-producing {gamma}{delta} T cells also were numerous, GM-CSF was exclusive to NKT17 cells and contributed to iNKT cell-mediated protection. These studies demonstrate how particular cellular interactions and responses of functional subsets of innate-like T cells contribute to protection from pathogenic lung infection.

immunology↗

bioRxiv2020

Epithelial HVEM promotes basement membrane synthesis and intraepithelial T cell survival and migration

Intraepithelial T cells (IET) provide continuous surveillance of the intestinal epithelium, but little was known about how epithelial-derived signals regulate the IET population. We show that epithelial expression of the herpes virus entry mediator (HVEM), a member of the TNF receptor superfamily (TNFRSF), maintained the survival of small intestine IET, especially innate-like TCR{beta}+ cells lacking CD4 and CD8{beta}. Patrolling movement of all CD8+ IET also was impaired in the absence of HVEM. HVEM-deficient epithelial cells exhibited downregulation of synthesis of basement membrane components, including collagen IV. Collagen IV supported IET survival in vitro via interactions with {beta}1 integrins expressed by the IET; absence of {beta}1 integrins decreased some IET subsets. Therefore, these data define a circuit whereby epithelial cells regulate intestine resident T lymphocyte populations through basement membrane synthesis.

immunology↗