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

Area of Science:

• Oncology
• Immunotherapy
• Cancer Biology

Background:

• Desmoplastic stroma in solid tumors poses a significant barrier to T cell-based immunotherapies.
• The precise mechanisms by which this stromal barrier impedes anti-tumor immunity are not fully understood.

Approach:

• Researchers utilized Chimeric Antigen Receptor (CAR) T cells targeting fibroblast activation protein (FAP), which is overexpressed on cancer-associated fibroblasts (CAFs).
• Established desmoplastic pancreatic tumors were treated with FAP-targeted CAR T cells to assess their impact on the tumor microenvironment and therapeutic efficacy.

Key Points:

• Depletion of FAP+ CAFs led to the degradation of the desmoplastic matrix, compromising tumor structural integrity.
• This stromal disruption sensitized previously resistant tumors to subsequent therapies, including mesothelin-targeted CAR T cells and anti-PD1 antibodies.
• The approach reversed immune exclusion, facilitated T cell extravasation and invasion, reduced myeloid cell accumulation, and promoted infiltration of endogenous CD8+ T cells and NK cells.

Conclusions:

• Targeting the desmoplastic stroma via FAP+ CAFs is a viable strategy to enhance the efficacy of immunotherapies.
• Combining stroma-targeting and tumor-targeting therapies holds promise for treating resistant solid tumors and warrants clinical investigation.