The Educational Program of Macrophages toward a Hyperprogressive Disease-Related Phenotype Is Orchestrated by Tumor-Derived Extracellular Vesicles

Abstract

Hyperprogressive disease (HPD), an aggressive acceleration of tumor growth, was observed in a group of cancer patients treated with anti-PD1/PDL1 antibodies. The presence of a peculiar macrophage subset in the tumor microenvironment is reported to be a sort of “immunological prerequisite” for HPD development. These macrophages possess a unique phenotype that it is not clear how they acquire. We hypothesized that certain malignant cells may promote the induction of an “HPD-related” phenotype in macrophages. Bone-marrow-derived macrophages were exposed to the conditioned medium of five non-small cell lung cancer cell lines. Macrophage phenotype was analyzed by microarray gene expression profile and real-time PCR. We found that human NSCLC cell lines, reported as undergoing HPD-like tumor growth in immunodeficient mice, polarized macrophages towards a peculiar pro-inflammatory phenotype sharing both M1 and M2 features. Lipid-based factors contained in cancer cell-conditioned medium induced the over-expression of several pro-inflammatory cytokines and the activation of innate immune receptor signaling pathways. We also determined that tumor-derived Extracellular Vesicles represent the main components involved in the observed macrophage re-education program. The present study might represent the starting point for the future development of diagnostic tools to identify potential hyperprogressors.

Exploring the possible link between the spike protein immunoglobulin G4 antibodies and cancer progression

“…Another possible way that IgG4 antibodies could reduce the effector functions of other cancer-targeting antibodies is by interacting with FcγRIIB receptors [57]. FcγRs are either activating or inhibitory in their function.…”

“…Currently, FcγRIIB receptors are the only known inhibitory ones. IgG4 antibodies happen to bind to FcγRIIB receptors with either similar or higher affinity than the other subclasses of IgG antibodies [57]. Therefore, IgG4's ability to interact with FcγRIIB receptors could allow them to reduce the desired effector functions of other subclasses of antibodies, even if such antibodies are still binding to activating receptors.…”

Impact of in vitro SARS-CoV-2 infection on breast cancer cells

“…After 24 h, mRNA was extracted using Direct-zol™ RNA MicroPrep (Zymo Research, Irvine, CA, USA) and reverse-transcribed with a High-Capacity RNA-to-cDNA Kit (Applied Biosystems, Thermo Fisher Scientific, Waltham, MA, USA) according to the manufacturer's instructions. Real-time PCR was performed as described in 58 using the following TaqMan® gene expression assays (Applied Biosystems, Thermo Fisher Scientific, Waltham, MA, USA): BCL2 (Hs04986394_ s1), PGR (Hs01556702_m1) and Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH, Hs02786624_g1). The mRNA level was normalized to that of GAPDH.…”

“…The mRNA level was normalized to that of GAPDH. The expression data were analyzed by the 2 -ΔCt method 58,59 . MCF7 cells were seeded in 96-well plates (3 × 10 4 cells/well) in complete medium and allowed to adhere overnight at 37 °C with 5% CO 2 to 80% confluence.…”