Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors

Abstract 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.…

• CR
  Cancer Research Institute

  Award: CRI4168
• UO
  University of Pennsylvania

  Awards: P30DK050306, P30 CA016520
• AC
  Abramson Cancer Center

  Award: P30 CA016520
• NI
  National Institutes of Health

  Awards: P30 CA016520, P30DK050306, CA016520
• NC
  National Cancer Institute

  Awards: P30 CA016520, CA016520, P01 CA217805, P30DK050306