Ghasemi et al. engineered DC progenitors expressing IL-12 and a non-signaling receptor (EVIR) targeting GD2, which promoted uptake of GD2+ cancer cells and their EVs. T cell activation by the DCs was dependent on MHC-I presentation by cancer cells, indicating cross-dressing as the primary mode for DC antigen display. IL-12+EVIR+ progenitor DCs (but not moDCs) synergized with anti-PD-1 in ICB-non-responsive models, enhancing CD8+ T cell infiltration and M1 polarization. In a B16 model with heterogeneous antigen expression, GD2-targeted EVIR+ DCs enhanced T cell activation against non-target cells to control tumor growth.
Contributed by Morgan Janes
ABSTRACT: Cancer immunotherapy using dendritic cells (DC) pulsed ex vivo with tumour antigens is considered safe, but its clinical efficacy is generally modest. Here we engineer DC progenitors (DCP), which can replenish conventional type 1 DCs (cDC1) in mice, to constitutively express IL-12 together with a non-signalling chimeric receptor, termed extracellular vesicle-internalizing receptor (EVIR). By binding to a bait molecule (GD2 disialoganglioside) expressed on cancer cells and their EVs, the EVIR enforces EV internalization by cDC1 to promote their cross-dressing with preformed, tumour-derived MHCI-peptide complexes. Upon systemic deployment to mice, the engineered DCPs cause only mild and transient elevation of liver enzymes, acquire tumour-derived material, engage tumour-specific T cells, and enhance the efficacy of PD-1 blockade in an immunotherapy-resistant melanoma model comprising both GD2-positive and -negative cancer cells, without the need for ex vivo antigen pulsing. These results indicate that EVIR-engineered DCPs may avert the positive selection of antigen-negative cancer cells, potentially addressing a critical limitation of immunotherapies targeting defined tumour antigens.
Author Info: (1) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer
Author Info: (1) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (2) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (3) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (4) Laboratory of Metabolic Signaling, Institute of Bioengineering, EPFL, Lausanne, Switzerland. (5) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (6) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (7) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (8) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (9) Animal Modeling Facility, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. (10) Animal Modeling Facility, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. (11) Department of Oncology, University of Lausanne (UNIL), Lausanne, Switzerland. Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland. (12) Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. Department of Oncology, Geneva University Hospital (HUG), Geneva, Switzerland. Center for Translational Research in Onco-Hematology, University of Geneva (UNIGE), Geneva, Switzerland. (13) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. michele.depalma@epfl.ch. Agora Cancer Research Center, Lausanne, Switzerland. michele.depalma@epfl.ch. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. michele.depalma@epfl.ch.
