Basically, seed tumors with IFN-1 using targeted RNA nanomolecules (that accumulated in the lungs in this case where they modeled lung cancers). This converts t

Basically, seed tumors with IFN-1 using targeted RNA nanomolecules (that accumulated in the lungs in this case where they modeled lung cancers). This converts the tumor microenvironment from one hostile to immune cells to one where immune cells are now active and on the hunt for tumor specific neoantigens. The one open question I wish they would get at is the exact sentization mechanism behind the PD-L1 inhibitor and IFN-1 response. The idea is that cancer cells have selective pressure to hide from the immune system and one way of doing that is presenting this PD-1 receptor to the PD-L1 ligand on the immune cell, an interaction that keeps the cancer cell from being killed and one that PD-L1 inhibitor drugs target to enable tumor cells to now be visible to the immune system (as they output a lot of screwed up things that are otherwise visible to the immune system as "not self"). They tested tumors that aren't sensitive to pd-l1 inhibition so presumably evading immune surveillance another way instead of presenting PD-1, and then found them to then be sensitive to PD-L1. It could be that within a tumor there are subclonal cells that do express PD-1 but are otherwise protected from PD-L1 inhibitiion having any effect from the hostile tumor microenvironment keeping immune surveillance from operating normally anyhow. Induce the immune response, now the T cell is in the area for PD-L1 inhibition to work. Another possibility is that the IFN-1 induction leads to PD-1 now being expressed by cells that didn't do it previously. Authors didn't explore this though. Probably would take more experiments and mice are expensive and time consuming. It could be answered by single cell RNA sequencing of these unresponsive tumors and seeing if there is some subset of cryptic tumor cells that do express PD-1 already before IFN-1 induction. As well as measuring expression after IFN-1 induction (maybe several timepoints to measure change in gene expression profile in the tumor population, if any)