Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors.
Zebin XiaoLeslie ToddLi HuangEstela Noguera-OrtegaZhen LuLili HuangMeghan KoppYue LiNimisha PattadaWenqun ZhongWei GuoJohn SchollerMaria LiousiaCharles-Antoine AssenmacherCarl H JuneSteven M AlbeldaEllen PuréPublished in: Nature communications (2023)
The desmoplastic stroma in solid tumors presents a formidable challenge to immunotherapies that rely on endogenous or adoptively transferred T cells, however, the mechanisms are poorly understood. To define mechanisms involved, here we treat established desmoplastic pancreatic tumors with CAR T cells directed to fibroblast activation protein (FAP), an enzyme highly overexpressed on a subset of cancer-associated fibroblasts (CAFs). Depletion of FAP + CAFs results in loss of the structural integrity of desmoplastic matrix. This renders these highly treatment-resistant cancers susceptible to subsequent treatment with a tumor antigen (mesothelin)-targeted CAR T cells and to anti-PD-1 antibody therapy. Mechanisms include overcoming stroma-dependent restriction of T cell extravasation and/or perivascular invasion, reversing immune exclusion, relieving T cell suppression, and altering the immune landscape by reducing myeloid cell accumulation and increasing endogenous CD8 + T cell and NK cell infiltration. These data provide strong rationale for combining tumor stroma- and malignant cell-targeted therapies to be tested in clinical trials.
Keyphrases
- clinical trial
- single cell
- cell therapy
- nk cells
- dendritic cells
- randomized controlled trial
- electronic health record
- bone marrow
- mesenchymal stem cells
- small molecule
- immune response
- big data
- phase ii
- extracellular matrix
- machine learning
- artificial intelligence
- binding protein
- young adults
- open label
- protein protein
- childhood cancer