PREreviews of “Acquisition of an immunosuppressive microenvironment after CAR-T therapy drives T-cell dysfunction and resistance”

Skip to preprint details Skip to PREreviews

Acquisition of an immunosuppressive microenvironment after CAR-T therapy drives T-cell dysfunction and resistance

by Marianna Ponzo, Lorenzo Drufuca, Chiara Buracchi, Marco M. Sindoni, Silvia Nucera, Cristina Bugarin, Ramona Bason, Grazisa Rossetti, Raoul Bonnal, Cristian Meli, Benedetta Rambaldi, Federico Lussana, Silvia Ferrari, Alex Moretti, Giulia Risca, Christian Pellegrino, Markus G. Manz, Stefania Galimberti, Alessandro Rambaldi, Giuseppe Gaipa, Andrea Biondi, Massimiliano Pagani, and Chiara F. Magnani

Posted: December 22, 2024
Server: bioRxiv
DOI: 10.1101/2024.12.20.629119

Abstract

Chimeric antigen receptor (CAR) T cells targeting CD19 induce durable responses in B-cell acute lymphoblastic leukemia (B-ALL). However, the contribution of the tumor microenvironment to the therapeutic response after CAR-T cell treatment remains incompletely understood. We performed single-cell RNA sequencing and spectral flow cytometry-based analyses of bone marrow-resident immune cells from B-ALL patients before and after CAR T-cell treatment. We observed profound changes in the microenvironment in response to CAR T cell-mediated inflammation, including an increase in myeloid cells. Significant induction of the IFN response, hypoxia, and TGF-β-signaling was associated with expansion of myeloid-derived suppressor cells (MDSCs) and endogenous exhausted CD8+ T cells. PD1 expression in endogenous T cells post-treatment was associated with a lack of durable response in the cohort of patients analyzed. Further, we revealed that HIF1α, VEGF, and TGFBR2 are key players in the intercellular communication between CAR T cells and the immune niche, driving widespread T-cell dysfunction. Infusion of anti-CD19 CAR T cells led to increased accumulation of human MDSCs, exacerbation of a hypoxic environment and T-cell exhaustion in HSPC-humanized mice bearing a human tumor. In conclusion, CAR T-cell-mediated myeloid activation is associated with pathways of immune dysregulation that may antagonize the effects of therapy.

Key points

The tumor immune context post-treatment affects CAR T-cell fate and endogenous immunity in B-cell acute lymphoblastic leukemia.
IFN response, hypoxia, and TGF-β-signaling result in endogenous T-cell exhaustion and compromise CAR T-cell efficacy.

Read the preprint

1 PREreview

Write a PREreview Request a PREreview

PREreview by Alex To et al. of the ASAPbio Immunology Crowd

Authored by Alex To, Chen Yang, Julia Hansen, Marina Schernthanner, Randa Salah Gomaa Mahmoud, and 2 other authors of the ASAPbio Immunology Crowd
Brief summary of the study - a sentence summarizing the study and general comments that apply across the full paper
- By investigating B-ALL patients before and after CAR T cell treatment using flow cytometry, hematology analyses and scRNA-seq, the authors give new insights into the tumor…
Read the PREreview by Alex To et al. of the ASAPbio Immunology Crowd

PREreviews of Acquisition of an immunosuppressive microenvironment after CAR-T therapy drives T-cell dysfunction and resistance

1 PREreview