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][1] [1]: /lookup/volpage/11/2945?iss=12

中文翻译：

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阻断短型 Ron 通过积累破坏免疫抑制的干细胞样 CD4+ T 细胞来消除乳腺癌转移


免疫疗法具有预防和治疗转移性乳腺癌的潜力，但迫切需要增强免疫介导杀死转移性肿瘤的策略。我们报告称，Ron 激酶的配体独立亚型（SF-Ron）是增强免疫浸润和根除转移性肿瘤的关键靶点。宿主特异性删除 SF-Ron 会导致淋巴细胞募集至微转移，增强肿瘤特异性 T 细胞反应，并几乎消除小鼠乳腺癌转移。缺乏宿主 SF-Ron 会导致具有 I 型分化潜力的干细胞样 TCF1+ CD4+ T 细胞在转移灶中积聚并防止转移瘤生长。肿瘤特异性 CD8+ T 细胞相应增加，这也是消除肺转移所必需的。用 Ron 激酶抑制剂治疗小鼠可增加肿瘤特异性 CD8+ T 细胞并防止转移性生长。这些数据为寻求小分子 Ron 激酶抑制剂预防和治疗转移性乳腺癌提供了强有力的临床前依据。意义：SF-Ron 促进抗肿瘤免疫反应的发现具有重要的临床意义。针对全长 Ron 的治疗性抗体可能对免疫疗法无效；此类抗体在试验中疗效不佳可能是由于它们无法阻断 SF-Ron。我们的数据保证了针对 SF-Ron 的抑制剂与免疫疗法相结合的试验。本文在本期专题中突出显示，[p. 11]。 2945][1][1]：/lookup/volpage/11/2945?iss=12