Unknown

Dataset Information

0

Blocking Short-Form Ron Eliminates Breast Cancer Metastases through Accumulation of Stem-Like CD4+ T Cells That Subvert Immunosuppression.


ABSTRACT: Immunotherapy has potential to prevent and treat metastatic breast cancer, but strategies to enhance immune-mediated killing of metastatic tumors are urgently needed. We report that a ligand-independent isoform of Ron kinase (SF-Ron) is a key target to enhance immune infiltration and eradicate metastatic tumors. Host-specific deletion of SF-Ron caused recruitment of lymphocytes to micrometastases, augmented tumor-specific T-cell responses, and nearly eliminated breast cancer metastasis in mice. Lack of host SF-Ron caused stem-like TCF1+ CD4+ T cells with type I differentiation potential to accumulate in metastases and prevent metastatic outgrowth. There was a corresponding increase in tumor-specific CD8+ T cells, which were also required to eliminate lung metastases. Treatment of mice with a Ron kinase inhibitor increased tumor-specific CD8+ T cells and protected from metastatic outgrowth. These data provide a strong preclinical rationale to pursue small-molecule Ron kinase inhibitors for the prevention and treatment of metastatic breast cancer.

Significance

The discovery that SF-Ron promotes antitumor immune responses has significant clinical implications. Therapeutic antibodies targeting full-length Ron may not be effective for immunotherapy; poor efficacy of such antibodies in trials may be due to their inability to block SF-Ron. Our data warrant trials with inhibitors targeting SF-Ron in combination with immunotherapy. This article is highlighted in the In This Issue feature, p. 2945.

SUBMITTER: Lai SA 

PROVIDER: S-EPMC8800951 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

altmetric image

Publications

Blocking Short-Form Ron Eliminates Breast Cancer Metastases through Accumulation of Stem-Like CD4+ T Cells That Subvert Immunosuppression.

Lai Shu-Chin Alicia SA   Gundlapalli Harika H   Ekiz H Atakan HA   Jiang Amanda A   Fernandez Elvelyn E   Welm Alana L AL  

Cancer discovery 20211201 12


Immunotherapy has potential to prevent and treat metastatic breast cancer, but strategies to enhance immune-mediated killing of metastatic tumors are urgently needed. We report that a ligand-independent isoform of Ron kinase (SF-Ron) is a key target to enhance immune infiltration and eradicate metastatic tumors. Host-specific deletion of SF-Ron caused recruitment of lymphocytes to micrometastases, augmented tumor-specific T-cell responses, and nearly eliminated breast cancer metastasis in mice.  ...[more]

Similar Datasets

| S-EPMC4979590 | biostudies-literature
| S-EPMC3218405 | biostudies-literature
| S-EPMC7851020 | biostudies-literature
| S-EPMC5385617 | biostudies-literature
| S-EPMC11528712 | biostudies-literature
| S-EPMC4747350 | biostudies-literature
| S-EPMC5838354 | biostudies-literature
2024-09-16 | PXD052373 | Pride
| S-EPMC4101915 | biostudies-literature
| S-EPMC7503580 | biostudies-literature