Open AccessMyeloid cell‐based delivery of IFN‐γ reprograms the leukemia microenvironment and induces anti‐tumoral immune responses
Author(s) -
Mucci Adele,
Antonarelli Gabriele,
Caserta Carolina,
Vittoria Francesco Maria,
Desantis Giacomo,
Pagani Riccardo,
Greco Beatrice,
Casucci Monica,
Escobar Giulia,
Passerini Laura,
Lachmann Nico,
Sanvito Francesca,
Barcella Matteo,
Merelli Ivan,
Naldini Luigi,
Gentner Bernhard
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202013598
Subject(s) - tumor microenvironment , cancer research , immune system , cytotoxic t cell , biology , immunotherapy , leukemia , haematopoiesis , immunology , cd8 , tumor necrosis factor alpha , adoptive cell transfer , stem cell , myeloid , t cell , microbiology and biotechnology , biochemistry , in vitro
The immunosuppressive microenvironment surrounding tumor cells represents a key cause of treatment failure. Therefore, immunotherapies aimed at reprogramming the immune system have largely spread in the past years. We employed gene transfer into hematopoietic stem and progenitor cells to selectively express anti‐tumoral cytokines in tumor‐infiltrating monocytes/macrophages. We show that interferon‐γ (IFN‐γ) reduced tumor progression in mouse models of B‐cell acute lymphoblastic leukemia (B‐ALL) and colorectal carcinoma (MC38). Its activity depended on the immune system's capacity to respond to IFN‐γ and drove the counter‐selection of leukemia cells expressing surrogate antigens. Gene‐based IFN‐γ delivery induced antigen presentation in the myeloid compartment and on leukemia cells, leading to a wave of T cell recruitment and activation, with enhanced clonal expansion of cytotoxic CD8 + T lymphocytes. The activity of IFN‐γ was further enhanced by either co‐delivery of tumor necrosis factor‐α (TNF‐α) or by drugs blocking immunosuppressive escape pathways, with the potential to obtain durable responses.