Selective Display of a Chemoattractant Agonist on Cancer Cells Activates the Formyl Peptide Receptor 1 on Immune Cells**

Abstract

Current immunotherapeutics often work by directing components of the immune system to recognize biomarkers on the surface of cancer cells to generate an immune response. However, variable changes in biomarker distribution and expression can result in inconsistent patient response. The development of a more universal tumor‐homing strategy has the potential to improve selectivity and extend therapy to cancers with decreased expression or absence of specific biomarkers. Here, we designed a bifunctional agent that exploits the inherent acidic microenvironment of most solid tumors to selectively graft the surface of cancer cells with a formyl peptide receptor ligand (FPRL). Our approach is based on the pH(Low) insertion peptide (pHLIP), a unique peptide that selectively targets tumors in vivo by anchoring to cancer cells in a pH‐dependent manner. We establish that selectively remodeling cancer cells with a pHLIP‐based FPRL activates formyl peptide receptors on recruited immune cells, potentially initiating an immune response towards tumors.

Aiming the magic bullet: targeted delivery of imaging and therapeutic agents to solid tumors by pHLIP peptides

“…In addition to the targeted delivery of antigens, the surface display of cancer cell molecules that promote the recruitment of immune cells was investigated ( Sikorski et al, 2022 ). pHLIP was conjugated with a formyl peptide receptor ligand (FPRL) to form FPRL-pHLIP agent.…”

Tumor treatment by pHLIP-targeted antigen delivery

“…In addition to successful preclinical and clinical pHLIP-driven intracellular delivery of payloads to tumors (Cheng et al, 2014;Wyatt et al, 2018;Price et al, 2019;Sahraei et al, 2019;Gayle et al, 2021), pHLIPs allow extracellular targeting of cargo molecules for presentation at the surfaces of cells since a pHLIP peptide inserts across the membrane, translocating one terminus into the cytoplasm and leaving the other uninserted terminus in the extracellular space (Hunt et al, 1997;Reshetnyak et al, 2007;Andreev et al, 2010). It has been shown that a pH-dependent pHLIP-mediated decoration of cancer cells with DNP promotes ADCC (Wehr et al, 2020) and that a display of a chemoattractant agonist activates the formyl peptide receptor 1 on immune cells (Sikorski et al, 2022). An additional challenge for all of these immune approaches is to achieve effective presentation of the antigens.…”