Biology subjects

Viklund, M.

Publications and source records attributed to Viklund, M..

3 recordsLinked to original sources

bioRxiv2026

The solid tumor microenvironment changes the hierarchy of CD155 and CD112 receptors, shaping checkpoint blockade outcome

Reproducing a physiologically relevant tumor microenvironment in vitro is essential for developing effective immunotherapeutic treatments. By integrating the use of combinatorial receptor blockade and organoid models we provide a deep functional understanding of CD155 and CD112 receptors in solid tumors and their impact on cellular immunotherapy and infiltration. CD226 showed plasticity in response to the environment, being able to switch between CD155 and CD112 depending on the ligand availability. In addition, CD226 drove NK cell infiltration into tumor tissues via CD155 and CD112 ligation, with CD226-CD112 interaction specifically promoting migration from the periphery to the core. Downregulation of CD155 and TIGIT induced by the tumor microenvironment and previous drug exposure reduced the long-term efficacy of TIGIT blockade. Taken together, our findings point towards using CD112R blockade in primary tumors to simultaneously enhance NK cell killing activity and promote infiltration into the tumor core via CD226 and CD112 interaction. ONE SENTENCE SUMMARYTumors shape the hierarchy of CD155-CD112 receptors, reducing TIGIT blockade efficacy, while CD226 drives NK infiltration and shows binding plasticity

immunology↗

bioRxiv2022

The ketone body acetoacetate activates human neutrophils through FFA2R

Neutrophils express many surface receptors that sense environmental changes. One such sensor is FFA2R (free fatty acid receptor 2), a receptor that detects gut microbiota-derived short chain fatty acids. As such, FFA2R has been regarded as a molecular link between metabolism and inflammation. Our recent studies on FFA2R, using its endogenous agonist propionate in combination with allosteric modulators, have identified several novel aspects of FFA2R regulation. A recent study has also identified the ketone body acetoacetate as an endogenous ligand for mouse FFA2R. Whether human FFA2R also recognizes acetoacetate and how this recognition modulates human neutrophil functions has not been earlier investigated. In this study, we found that acetoacetate can induce a decrease of cAMP and translocation of {beta}-arrestin in cells overexpressing FFAR2. In addition, we show that similar to propionate, FFA2R specific allosteric modulators enhance acetoacetate-induced transient rise in cytosolic calcium, production of reactive oxygen species and cell migration in human neutrophils. In summary, we demonstrate that human neutrophils recognize the ketone body acetoacetate through FFA2R. Thus, our data further highlight the key role of FFA2R in inflammation and metabolism.

cell biology↗

bioRxiv2021

Structural determinants in the Staphylococcus aureus derived phenol-soluble modulin-α2 peptide required for neutrophil formyl peptide receptor activation

Highly pathogenic Staphylococcus aureus strains produce phenol-soluble modulins (PSMs), peptides which are formylated N-terminally. Nanomolar concentrations of PSM2 are recognized by formyl peptide receptor 2 (FPR2), but unlike the prototypic FPR2 agonist WKYMVM, PSM2 is a biased signaling agonist. A shortened N-terminal PSM2 variant, consisting of the five N- terminal residues, is selectively recognized by the closely related FPR1, showing that the C- terminal part of PSM2 confers FPR2 selectivity, while the N-terminal part may interact with the FPR1 binding site. In the present study, a combined pharmacological and genetic approach, involving primary neutrophils and engineered FPR "knock-in" and "knock-out" cells, was used to gain molecular insights into FPR1 and FPR2 recognition of formyl peptides and the receptor downstream signaling induced by these peptides. In comparison to the full-length PSM2, we show that the peptide in which the N-terminal part of PSM2 was replaced by fMIFL (an FPR1- selective peptide agonist) potently activates both FPRs for production of superoxide anions and {beta}- arrestin recruitment. A shortened analogue of PSM2 (PSM21-12), lacking the nine C-terminal residues activated both FPR1 and FPR2 to produce ROS, whereas {beta}-arrestin recruitment was only mediated through FPR1. However, a single amino acid replacement (Gly-2 to Ile-2) in PSM21-12 was sufficient to alter FPR2 signaling to include {beta}-arrestin recruitment, highlighting a key role of Gly-2 in conferring FPR2 biased signaling. In conclusion, we provide novel structural insights into FPR1 and FPR2 recognition as well as the signaling induced by interaction with formyl peptides derived from PSM2, originating from Staphylococcus aureus bacteria.

immunology↗