Bruecher, D. | bioRxiv Science

bioRxiv2025

Retargeted adenoviruses for local IgA and CD47 blocker production as a novel cancer therapy

Despite advances in IgG-based cancer immunotherapy, challenges remain in effectively engaging innate immune responses against solid tumors. Here, IgA antibodies hold promise due to their ability to activate neutrophils and macrophages. We present a novel retargeted adenovirus-mediated approach that transforms cancer cells into "biofactories" for localized production of monomeric or dimeric IgA antibodies and a CD47 blocker to potentiate the effect of IgA antibodies. With our approach tumor cells effectively produced IgA antibodies against tumor antigens such as EGFR or EpCAM and a soluble SIRP-Fc fusion protein, which blocks the CD47-SIRP axis. In a perfused tumor-on-a-chip model, locally produced IgA triggered neutrophil- and macrophage-mediated tumor cell killing, further potentiated by SIRP-Fc co-production. In FcRI-transgenic, tumor-bearing mice, intratumoral adenoviral injection induced strong local IgA and SIRP-Fc expression, immune cell infiltration, and more than 50% tumor volume reduction after a single treatment. We found that dimeric IgA exerts stronger effects than monomeric IgA, which is of particular interest since dimeric IgA necessitates a local production approach. Together, these results demonstrate that adenovirus-mediated, tumor-restricted delivery of IgA antibodies and CD47 blockade effectively engages innate immune mechanisms, providing a promising new avenue to enhance cancer immunotherapy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/686998v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@183dd88org.highwire.dtl.DTLVardef@452624org.highwire.dtl.DTLVardef@1cb10e8org.highwire.dtl.DTLVardef@c2fa85_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

Successful IL-12 cancer immunotherapy requires NK cell-derived CCL5 for anti-tumor DC-T cell crosstalk

T cell-directed cancer immunotherapy often fails to generate lasting tumor control. Harnessing additional effectors of the immune response against tumors may strengthen the clinical benefit of immunotherapies. Here, we demonstrate that therapeutic targeting of the IFN{gamma}-IL-12 pathway relies on the ability of a population of tissue-resident NK (trNK) cells to orchestrate an anti-tumor microenvironment. Particularly, utilizing an engineered adenoviral platform, we show that paracrine IL-12 enhances functional DC-CD8 T cell interactions to generate adaptive anti-tumor immunity. This effect depends on the abundance of trNK cells and specifically their capacity to produce the cDC1-chemoattractant CCL5. Failure to respond to IL-12 and other IFN{gamma}-inducing therapies such as immune checkpoint blockade in tumors with low trNK cell infiltration could be overcome by intra-tumoral delivery of CCL5. Our findings reveal a novel barrier for T cell-focused therapies and offer mechanistic insights into how T cell-NK cell-DC crosstalk can be enhanced to promote anti-tumor immunity and overcome resistance. SignificanceWe identified the lack of CCL5-producing, tissue-resident NK (trNK) cells as a barrier to T cell-focused therapies. While IL-12 induces anti-tumoral DC-T cell crosstalk in trNK cellrich tumors, resistance to IL-12 or anti-PD-1 in trNK cellpoor tumors can be overcome by the additional delivery of CCL5.

immunology↗