Low-dose carboplatin modifies the tumor microenvironment to augment CAR T cell efficacy in human prostate cancer models
- Author(s)
- Porter, LH; Zhu, JJ; Lister, NL; Harrison, SG; Keerthikumar, S; Goode, DL; Quezada Urban, R; Byrne, DJ; Azad, A; Vela, I; Hofman, MS; Neeson, PJ; Darcy, PK; Trapani, JA; Taylor, RA; Risbridger, GP;
- Journal Title
- Nature Communications
- Publication Type
- Research article
- Abstract
- Chimeric antigen receptor (CAR) T cells have transformed the treatment landscape for hematological malignancies. However, CAR T cells are less efficient against solid tumors, largely due to poor infiltration resulting from the immunosuppressive nature of the tumor microenvironment (TME). Here, we assessed the efficacy of Lewis Y antigen (Le(Y))-specific CAR T cells in patient-derived xenograft (PDX) models of prostate cancer. In vitro, Le(Y) CAR T cells directly killed organoids derived from androgen receptor (AR)-positive or AR-null PDXs. In vivo, although Le(Y) CAR T cells alone did not reduce tumor growth, a single prior dose of carboplatin reduced tumor burden. Carboplatin had a pro-inflammatory effect on the TME that facilitated early and durable CAR T cell infiltration, including an altered cancer-associated fibroblast phenotype, enhanced extracellular matrix degradation and re-oriented M1 macrophage differentiation. In a PDX less sensitive to carboplatin, CAR T cell infiltration was dampened; however, a reduction in tumor burden was still observed with increased T cell activation. These findings indicate that carboplatin improves the efficacy of CAR T cell treatment, with the extent of the response dependent on changes induced within the TME.
- Publisher
- Springer Nature
- Keywords
- Male; Animals; Humans; Carboplatin/pharmacology/therapeutic use; Tumor Microenvironment; T-Lymphocytes; *Prostatic Neoplasms/drug therapy; *Cancer-Associated Fibroblasts; Disease Models, Animal
- Department(s)
- Laboratory Research; Medical Oncology; Cancer Imaging; Pathology
- PubMed ID
- 37660083
- Publisher's Version
- https://doi.org/10.1038/s41467-023-40852-3
- Open Access at Publisher's Site
https://doi.org/10.1038/s41467-023-40852-3- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-11-21 05:54:25
Last Modified: 2023-11-21 05:55:40