Biology subjects

Mattsson, J.

Publications and source records attributed to Mattsson, J..

4 recordsLinked to original sources

bioRxiv2026

Leveraging TNFR2 for antitumour immunity: T reg depletion and myeloid reprogramming versus T cell costimulation

Although checkpoint inhibitors have revolutionized cancer treatment, responses are largely restricted to targeting CTLA-4 and PD-(L)1. TNFR2 has been identified as a target of interest, but a lack of understanding of whether agonists or blockers should be used, and whether Fc{gamma}R interactions promote effcacy, has hampered therapeutic antibody development. Here, we engineered two distinct -TNFR2 types: ligand-blocking Fc{gamma}R-engaging versus non-ligand-blocking agonist antibodies. Both showed potent anti-tumor effcacy across multiple syngeneic mouse tumor models and combined effectively with -PD-1. The ligand-blocking antibody depleted intratumoral T regs and reprogrammed the myeloid compartment, directing monocytes towards a pro-inflammatory macrophage and dendritic cell trajectory. Surprisingly, this effect depended on both inhibitory and activating Fc{gamma}Rs. In contrast, the agonist directly co-stimulated T and NK cells, through partially Fc{gamma}R-independent mechanisms. Both antibodies converged on activating tumor-specific CD8+ T cells mediating tumor rejection. Clinical assessment of both ligand-blocking (BI-1808) and agonist (BI-1910) -TNFR2 antibodies is currently ongoing. Graphical abstractO_LILigand-blocking anti-TNFR2 mAbs (BI-1808 and 3F10) deplete CCR8+ T regs and activate myeloid cells, remodeling the TME and leading to CD8+ T cell killing of cancer cells. T reg depletion and myeloid activation are mediated through interaction with activating Fc{gamma}Rs and the inhibitory Fc{gamma}RIIB, respectively. C_LIO_LIAgonist anti-TNFR2 mAbs (BI-1910 and 5A05) intrinsically agonize TNFR2 on T cells and NK cells, which is enhanced by Fc{gamma}RIIB crosslinking. The resulting broad lymphocyte activation mediates cancer cell killing. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/697572v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@3ecc17org.highwire.dtl.DTLVardef@c936a7org.highwire.dtl.DTLVardef@23189aorg.highwire.dtl.DTLVardef@243a05_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Cell therapy with IL-10-producing group 2 innate lymphoid cells suppresses Graft-versus-Host disease

IL-10 producing group 2 innate lymphoid cells (ILC210) have immunoregulatory functions, and limit harmful immune responses across various tissues. Despite their crucial roles in maintaining immune homeostasis, the cell therapy potential of human ILC210 has not been demonstrated, due to both limited numbers in human peripheral blood and lack of definitive markers for identification. Here, we isolate and expand circulating human ILC210, and assess their cell therapy potential in a humanized model of Graft-versus-Host Disease (GVHD). Cell therapy with human ILC210 decreased GVHD severity and prolonged survival of NOD-scid IL2R{gamma}null (NSG) mice. Adoptive transfer of ILC210 inhibited pathogenic T cell proliferation and intestinal infiltration, and suppressed CD4+ Th1 and CD8+ Tc1 cells in an IL-4 and IL-10 dependent manner. Critically, increased proportions of ILC2s did not correlate with higher rates of cancer relapse in HSCT recipients, and adoptive transfer of ILC210 did not compromise graft-versus-leukemic (GVL) effects in a humanized model. Finally, we identify CD49d and CD86 as novel markers that discriminate ILC210 from conventional ILC2s. Collectively, these findings demonstrate the potential of harnessing ILC210 in cell therapies for GVHD and other immune-driven pathologies.

immunology↗

bioRxiv2021

The ratio of cytotoxic lymphocytes to M2-like macrophages is prognostic in immunogenic tumors

Immune cells in the microenvironment shape tumor development and progression. The prognostic value of T-cell-based immune scores exceeds those of clinical parameters in colon cancer, but reflects only a part of the anti-tumor immune response. Here, we assessed 15 distinct immune cell classes and identified a simple prognostic signature based on pro- and anti-tumoral immune cells in the tumor microenvironment. The ratio of cytotoxic lymphocytes to tumor supportive macrophages predicted survival better than the state-of-art immune score in colon cancer and had the highest relative contribution to survival prediction when compared to established clinical parameters. This signature was prognostic also in other cancers with high mutation burden, such as those of the lung, bladder, esophagus, and melanomas, supporting broad clinical applicability. One Sentence SummaryThe CD8/M2 ratio in tumor tissue defines prognosis in immunogenic cancers

cancer biology↗

bioRxiv2020

Identification of a novel missense variant in SPDL1 associated with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite significant progress, the genetic determinants of this disease remain incompletely defined. Using next generation sequencing data from 752 individuals with sporadic IPF and 119,055 controls, we performed both variant- and gene-level analyses to identify novel IPF genetic risk factors. Our variant-level analysis revealed a novel rare missense variant in SPDL1 (NM_017785.5 p.Arg20Gln; p = 2.4 x 10-7, odds ratio = 2.87). This signal was independently replicated in the FinnGen cohort (combined p = 2.2 x 10-20), firmly associating this variant as a novel IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. Our results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need.

genetics↗