Aptamer Targeted Therapy Potentiates Immune Checkpoint Blockade in Triple-Negative Breast Cancer

Abstract

Background: Triple-negative breast cancer (TNBC) is a uniquely aggressive cancer with high rates of relapse due to resistance to chemotherapy, the current major option for treatment. TNBC expresses higher levels of programmed cell death-ligand 1 (PD-L1) compared to other breast cancers, providing the rationale for the recently approved immunotherapy with anti-PD-L1 monoclonal antibodies (mAbs). A huge effort is dedicated to identify actionable biomarkers that may allow for novel combination therapies with immune-checkpoint blockade in TNBC. Platelet-derived growth factor receptor β (PDGFRβ) is highly expressed in mesenchymal invasive TNBC, both on tumor cells and tumor microenvironment (TME). We recently proved that tumor growth and lung metastases are impaired in mouse models of human TNBC by a high efficacious PDGFRβ aptamer. Hence, we aimed at investigating the effectiveness of a novel combination treatment with the PDGFRβ aptamer and anti-PD-L1 mAbs in TNBC.Methods: The targeting ability of the anti-human PDGFRβ aptamer toward the murine receptor was verified by streptavidin-biotin assays and confocal microscopy, and its inhibitory function by transwell migration assays on PDGFRβ-positive cells. The anti-proliferative effects of the PDGFRβ aptamer/anti-PD-L1 mAbs combination was assessed in human MDA-MB-231 and murine 4T1 TNBC cells, both grown as monolayer or co-cultured with lymphocytes. Tumor cell lysis and cytokines secretion by lymphocytes were analyzed by LDH quantification and ELISA, respectively. Orthotopic 4T1 xenografts in syngeneic mice were used for dissecting the effect of aptamer/mAbs combination on tumor growth, metastasis and lymphocytes infiltration. Ex vivo analyses through immunohistochemistry, RT-qPCR and immunoblotting were performed. Results: We show that the PDGFRβ aptamer potentiates the anti-proliferative activity of anti-PD-L1 mAbs on both human and murine TNBC cells, according to its human/mouse cross-reactivity. Further, by binding to activated human and mouse lymphocytes, the aptamer enhances the anti-PD-L1 mAbs-induced cytotoxicity of lymphocytes against tumor cells. Importantly, the aptamer heightens the antibody efficacy in inhibiting tumor growth and lung metastases in a syngeneic mouse model by acting on both TME and cancer cells. Conclusion: Co-treatment of PDGFRβ aptamer with anti-PD-L1 mAbs is a viable strategy, thus providing for the first an evidence of the efficacy of PDGFRβ/PD-L1 co-targeting combination therapy in TNBC.

A phase 2 study of thalidomide for the treatment of radiation-induced blood-brain barrier injury

“…S12A). Because of the concern of possible off-target effects of imatinib mesylate, we also used a PDGFRβ-specific antagonist, a nuclease-resistant RNA-aptamer named Gint4.T, which can specifically bind to the PDGFRβ ectodomain, resulting in strong inhibition of ligand-dependent PDGFRβ receptor activation in cultured cells and in vivo ( 48 – 50 ), and our findings showed a persistent radiation-induced BBB leakage despite thalidomide treatment (Fig. 5, A, D, and E, and figs.…”

Integrated immune-related gene signature predicts clinical outcome for patients with Luminal B breast cancer

“…Evidence shows that CAF, which plays a key role in breast cancer progression, is in uenced by PDGFRB [42], which blocks invasive growth and migration in triple-negative breast cancer [43]. The immune-checkpoint blockade treatment with PDGFRB aptamer in triple-negative breast cancer [44] gives enlightenment in treating Luminal B breast cancer. This indicates that IGRS may have potential immunotherapy signi cance; however, more studies are needed for further exploration and validation.…”

Targeting triple-negative breast cancer with β1-integrin binding aptamer

“…Epidermal growth factor receptor (EGFR) (22)(23)(24)(25), platelet-derived growth factor receptor β (PDGFRβ) (26)(27)(28), nucleolin (29)(30)(31)(32)(33)(34)(35), CD133 (36), CD44 (37,38), epithelial cell adhesion molecule (EpCAM) (39,40), CD49c (41) and Tenascin-C (42) binding aptamers have shown the potential of selective delivery of therapeutic agents to TNBC in vitro and in vivo.…”