Local, multimodal intralesional therapy renders distant brain metastases susceptible to PD-L1 blockade in a preclinical model of triple-negative breast cancer

Abstract

Abstract Despite recent progress in therapeutic strategies, prognosis of metastatic triple-negative breast cancer (TNBC) remains dismal. Evidence suggests that the induction and activation of tumor-residing conventional type-1 dendritic cells (cDC1s) is critical for the generation of CD8+ T cells that mediate the regression of mammary tumors and potentiate anti-PD-1/PD-L1 therapeutic efficacy. However, it remains unknown whether this strategy is effective against metastatic TNBC, which is poorly responsive to immunotherapy. Here, using a mouse model of TNBC, we established orthotopic mammary tumors and brain metastases, and treated mammary tumors with in situ immunomodulation (ISIM) consisting of intratumoral injections of Flt3L to mobilize cDC1s, local irradiation to induce immunogenic tumor cell death, and TLR3/CD40 stimulation to activate cDC1s. ISIM treatment of the mammary tumor increased circulating T cells with effector phenotypes, and infiltration of CD8+ T cells into the metastatic brain lesions, resulting in delayed progression of brain metastases and improved survival. Furthermore, although anti-PD-L1 therapy alone was ineffective against brain metastases, ISIM overcame resistance to anti-PD-L1 therapy, which rendered these tumor-bearing mice responsive to anti-PD-L1 therapy and further improved survival. Collectively, these results illustrate the therapeutic potential of multimodal intralesional therapy for patients with unresectable and metastatic TNBC.