I think to go from a Gothic 19th century to a depressingly melancholic 22nd Century (and somewhat believable) environment was a great move. You can see the developers want to keep us fresh. Maybe not even just us, but themselves.
They're not a AAA studio that gets told to make mildly varying clones. They work for themselves and like most people; don't like doing the same job over and over
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I feel that in keeping with tradition, Frictional will go for a totally different setting for any new game they work on. That could be anywhere from space (possible Cliché, I know) to another world, to 20th century earth, to an underground world. So many possibilities.
They may tone down the horror to almost nothing, in search of a greater story.
Until they spill the beans (which probably won't be for a while) we can guess until the cows come home.