Abstract
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.
Highlights
The immunosuppressive microenvironment surrounding tumor cells represents a key cause of treatment failure
To evaluate the antitumor potential of cytokines in the context of our hematopoietic stem and progenitor cells (HSPC) gene therapy platform (De Palma et al, 2008; Escobar et al, 2014), lineage-negative HSPC from CD45.1 donor mice were transduced with lentiviral vectors expressing either mouse IFN-c, tumor necrosis factor-a (TNF-a), or a biologically inactive variant of human NGFR under the control of the Tie2e/p and microRNA 126/-130a target sequences (Fig EV1A and B)
No significant hematologic abnormalities were observed compared with controls, except a minor T cell reduction in the tumor necrosis factor (TNF)-a group, suggesting specificity of gene expression control by the miRNA-regulated Tie2e/p cassette (Fig EV1C and E), confirmed by the modest up-regulation of IFN-c-responsive genes in the tissues, without altering blood biochemical parameters and with barely detectable IFN-c levels in the plasma of engrafted mice (Fig EV1F–H)
Summary
The immunosuppressive microenvironment surrounding tumor cells represents a key cause of treatment failure. 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-c (IFN-c) 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-c and drove the counter-selection of leukemia cells expressing surrogate antigens. Gene-based IFN-c 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-c was further enhanced by either co-delivery of tumor necrosis factor-a (TNF-a) or by drugs blocking immunosuppressive escape pathways, with the potential to obtain durable responses
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