M6L8 Importance of targeting the stroma

  • Popular cancer models contributing to the bulk of the oncology literature lacks authentic stromal architecture

    • One tumour type has human like architecture in mice, but unpopular - likely as drugs do not work using in this model (however this is due to it being closer to human architecture and drug delivery here would be more authentic)

  • Stroma can act as a barrier to drug delivery or have immunomodulatory effects

  • Lack of CAFs in animal models vs humans, upon adding CAFs to animal tumour models then immunotherapies and cancer vaccines were less efficacious

  • An authentic representation of a solid tumour is that it is mostly stroma with islands of cancer cells, capillaries infiltrate the stroma and immune cells often are at the periphery

  • There is still ECM in liquid tumours, some around the cells at least

  • Cancer cells can not survive without stroma, the cells grown in vitro are abnormal in this sense as they can grow on plastic

  • ECM is more than a mechanical substrate - crosslinking enhances stiffness, signalling through ECM binding proteins driving proliferation/motility, CAFs and CAMs remodel the ECM…

    • Cross-linking enzymes eg lysyl hydroxylase (LOXL) increase stiffness

  • A problem with targeting ECM - if someone has pathology elsewhere in the body (fibrosis, inflammation, wounds…) then there will be off-target effects

  • TGFb - initially anti-timour and has pro-tumour in chronic cancer

    • TGFb are mostly expressed by stromal cells - it gets tethered to collagen in a protective ‘cage’ of LAP which creates a ‘memory’ of the tumour, the TBFb can get released/activated again by proteases or mechanical effects due to integrin binding from other cells even after the tumour cells are eliminated

  • Approaches to target fibroblasts include mAbs, OVs, bispecific Abs, vaccines, CAR-T… but it is difficult to target CAFs specifically and avoid off target effects as fibroblasts are all over the body

    • Fibroblast activation protein alpha (FAP-a) could be targeted?

  • Fibroblasts have ‘functional preferences’ depending on where they are in the TME

    • Antigen presenting CAFs are of emerging interest

    • Interest in reprogramming fibroblasts

  • Macrophages often do many of the same functions as fibroblasts - redundancy in the TME