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

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.

Intratumoral delivery of immunotherapy to treat breast cancer: current development in clinical and preclinical studies

“…Additionally, increasing radiotherapy treatments to three and performing surgery only one day after poly(I:C)/aCD40 treatment both independently enhanced survival in mice bearing orthotopic 4T1-luc tumors ( 120 ). Prior studies with this ISIM treatment in the primary treatment setting demonstrated that it increased frequencies of activated, effector CD4+ and CD8+ T cells in AT-3 murine tumors ( 114 ) and decreased PMN-MSDCs in AT-3 and 4T1 BC murine tumors ( 115 ).…”

Preclinical models to understand the biology and to discover new targets in brain metastases

“…The model consisted in the tumor inoculation in mammary fat pad and intracardiac injection of AT-3 cells (a primary mammary gland carcinoma of a transgenic mice). The findings were that in situ induction and activation of dendritic cells (cDC1s) by intratumoral injection of FMS-related tyrosine kinase 3 ligand (FLT3-L), mammary tumor irradiation and injection of toll-like receptor 3 (TLR3)/ CD40 at the peritumoral site leads into the infiltration of CD8þ T cells in distant nonirradiated central nervous system lesions [11]. Importantly, this treatment initiates systemic antitumor immunity, delays the progression of established TNBC BM, and renders them responsive to anti-PDL1 therapy to improve survival [11].…”

“…The findings were that in situ induction and activation of dendritic cells (cDC1s) by intratumoral injection of FMS-related tyrosine kinase 3 ligand (FLT3-L), mammary tumor irradiation and injection of toll-like receptor 3 (TLR3)/ CD40 at the peritumoral site leads into the infiltration of CD8þ T cells in distant nonirradiated central nervous system lesions [11]. Importantly, this treatment initiates systemic antitumor immunity, delays the progression of established TNBC BM, and renders them responsive to anti-PDL1 therapy to improve survival [11]. Another preclinical BCBM mouse model has been used to test the combination of doxorubicin, a chemotherapy drug that induces between other effects senescence, with anti-PD1 to improve the efficacy of immunotherapy.…”

“…Regarding immunotherapy, the use of immune checkpoint inhibitors (ICI) such as anti-programmed death-ligand 1 (PD-L1) has revolutionized the treatment landscape of patient with cancer [10]. A new approach using in situ immunomodulation (ISIM) has been tried in a TNBC BM immunocompetent mouse model (female C57BL/6, 7–9 weeks) [11]. The model consisted in the tumor inoculation in mammary fat pad and intracardiac injection of AT-3 cells (a primary mammary gland carcinoma of a transgenic mice).…”

Recent Progress on Therapeutic Vaccines for Breast Cancer

“…Food and Drug Administraion (FDA) has approved a number of ISV-based cancer immunotherapies, such as Bacilus Calmette-Guerin (BCG) for in situ vaccination, toll-like receptor agonists for in situ vaccination, oncolytic virus for in situ vaccination, and in situ vaccination with cytokines and immune checkpoint blockade. ISV involves manipulation of intratumoral immune cells by injecting immunomodulators ( 89 ) and local ablative therapies which are used to release tumor antigens from the therapy-killed tumor cells ( 90 ). Besides, local treatment with vaccines and adjuvant is another option to provoke immune system in situ ( 91 ).…”