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Published on: November 28, 2019
Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid
Zebin Xiao1, Leslie Todd1, Li Huang1
1Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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. 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.
Insights
Targeting cancer-associated fibroblasts (CAFs) with FAP-targeted CAR T cells reshapes the tumor microenvironment. This approach enhances susceptibility to subsequent immunotherapies like mesothelin-targeted CAR T cells and anti-PD-1 therapy.
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 therapy remain incompletely understood.
Purpose of the Study:
- To investigate the role of cancer-associated fibroblasts (CAFs) in mediating resistance to immunotherapy.
- To explore the therapeutic potential of targeting fibroblast activation protein (FAP) on CAFs.
Main Methods:
- Treatment of established desmoplastic pancreatic tumors with chimeric antigen receptor (CAR) T cells targeting FAP.
- Assessment of the impact of FAP+ CAF depletion on tumor structure and immune cell infiltration.
- Evaluation of subsequent treatment efficacy with mesothelin-targeted CAR T cells and anti-PD-1 antibody therapy.
Main Results:
- Depletion of FAP+ CAFs disrupted the desmoplastic matrix, increasing tumor susceptibility to immunotherapy.
- Targeting FAP+ CAFs overcame stroma-dependent T cell exclusion and suppression.
- This strategy promoted infiltration of endogenous CD8+ T cells and NK cells while reducing myeloid cell accumulation.
Conclusions:
- Targeting the desmoplastic stroma via FAP+ CAFs is a viable strategy to enhance immunotherapy efficacy.
- Combining stroma-targeting and tumor cell-targeting therapies offers a promising approach for treatment-resistant cancers.
- These findings support clinical trials combining FAP-targeted therapies with other immunotherapies.
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