Leptomeningeal anti-tumor immunity follows unique signaling principles.
Ján RemšíkXinran TongRussell Z KunesMin Jun LiAhmed OsmanKiana ChabotUgur T SenerJessica A WilcoxDanielle IsakovJenna SnyderTejus A BaleRonan ChalignéDana Pe'erAdrienne A BoirePublished in: bioRxiv : the preprint server for biology (2023)
Metastasis to the cerebrospinal fluid (CSF)-filled leptomeninges, or leptomeningeal metastasis (LM), represents a fatal complication of cancer. Proteomic and transcriptomic analyses of human CSF reveal a substantial inflammatory infiltrate in LM. We find the solute and immune composition of CSF in the setting of LM changes dramatically, with notable enrichment in IFN-γ signaling. To investigate the mechanistic relationships between immune cell signaling and cancer cells within the leptomeninges, we developed syngeneic lung, breast, and melanoma LM mouse models. Here we show that transgenic host mice, lacking IFN-γ or its receptor, fail to control LM growth. Overexpression of Ifng through a targeted AAV system controls cancer cell growth independent of adaptive immunity. Instead, leptomeningeal IFN-γ actively recruits and activates peripheral myeloid cells, generating a diverse spectrum of dendritic cell subsets. These migratory, CCR7+ dendritic cells orchestrate the influx, proliferation, and cytotoxic action of natural killer cells to control cancer cell growth in the leptomeninges. This work uncovers leptomeningeal-specific IFN-γ signaling and suggests a novel immune-therapeutic approach against tumors within this space.
Keyphrases
- dendritic cells
- cerebrospinal fluid
- papillary thyroid
- immune response
- regulatory t cells
- squamous cell
- single cell
- squamous cell carcinoma
- induced apoptosis
- lymph node metastasis
- cell proliferation
- mouse model
- drug delivery
- oxidative stress
- peripheral blood
- bone marrow
- acute myeloid leukemia
- transcription factor
- label free
- metabolic syndrome
- anti inflammatory
- cancer therapy