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William J. Gradishar, MD, FACP, FASCO
William J. Gradishar, MD, FACP, FASCO
Posted: Wednesday, November 20, 2024
The results of a study presented at the 2024 Society for Immunotherapy of Cancer (SITC) Annual Meeting (Abstract 826) found that a TROP2/claudin program mediates immune exclusion and thus hinders the effectiveness of checkpoint blockade therapy in breast cancer. Bogang Wu, PhD, of Harvard Medical School, Boston, and colleagues noted that the former protein may be targeted to enhance immunotherapy response.
“Antibody-drug conjugates targeting TROP2 are emerging as paradigm-changing drugs,” the investigators commented. “[However,] the therapeutically relevant mechanisms of TROP2 itself [previously] remained unknown.”
In this study, the investigators performed loss-of-function analyses in multiple syngeneic mouse mammary tumor models. The essential domains that enable TROP2 tumor-promoting activity were mapped via the reconstitution of truncated TROP2 mutants into CRISPR knockout cells. Using flow cytometry for tumor-infiltrating lymphocytes, tissue histology, and immunofluorescence, the investigators assessed the tumor microenvironment. Data from patients who underwent immune checkpoint inhibitor therapy were used to test hypotheses from the preclinical findings.
According to the investigators, in triple-negative breast cancer, TROP2 mediated a mechanism of immune exclusion via an association with the essential tight junction protein claudin-7. They found TROP2 expression to be inversely correlated with T-cell infiltration and strongly associated with outcomes. Based on in vivo loss-of-function and reconstitution experiments, TROP2 was sufficient to drive tumor progression in a CD8 T-cell–dependent manner; its loss appeared to deregulate expression and localization of multiple claudins, enabling T-cell infiltration.
In a humanized TROP2 syngeneic triple-negative breast cancer model, treatment with the TROP2-directed antibody-drug conjugate sacituzumab govitecan-hziy seemed to induce an anti–PD-1 response associated with broad immune cell activation. The investigators noted that TROP2 is highly associated with failure to respond to anti–PD-1 therapy in human breast cancer.
Disclosure: No information regarding conflicts of interest was provided.
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