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Modern cancer therapy: cryoablation meets immune checkpoint blockade.

ABSTRACT: Cryoablation, as a minimally invasive technology for the treatment of tumors, destroys target tumors with lethal low temperatures. It simultaneously releases a large number of tumor-specific antigens, pro-inflammatory cytokines, and nucleoproteins, known as "danger signals", activating the body's innate and adaptive immune responses. However, tumor cells can promote the inactivation of immune effector cells by reprogramming immune checkpoints, leading to the insufficiency of these antigens to induce an immune response capable of eradicating the tumor. Immune checkpoint blockers rejuvenate exhausted T cells by blocking immune checkpoints that induce programmed death of T cells, and are therefore considered a promising therapeutic strategy to enhance the immune effects of cryoablation. In this review, we provide a detailed explanation of the immunological mechanisms of cryoablation and articulate the theoretical basis and research progress of the treatment of cancer with cryoablation combined with immune checkpoint blockers. Preliminary data indicates that this combined treatment strategy exhibits good synergy and has been proven to be safe and effective.

SUBMITTER: Liu Q

PROVIDER: S-EPMC10881233 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Modern cancer therapy: cryoablation meets immune checkpoint blockade.

Liu Qi Q Zhang Chunyang C Chen Xuxin X Han Zhihai Z

Frontiers in oncology 20240207

Cryoablation, as a minimally invasive technology for the treatment of tumors, destroys target tumors with lethal low temperatures. It simultaneously releases a large number of tumor-specific antigens, pro-inflammatory cytokines, and nucleoproteins, known as "danger signals", activating the body's innate and adaptive immune responses. However, tumor cells can promote the inactivation of immune effector cells by reprogramming immune checkpoints, leading to the insufficiency of these antigens to in ...[more]

PMID: 38384806

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Project description:BackgroundTriple-negative breast cancer (TNBC) is a uniquely aggressive cancer with high rates of relapse due to resistance to chemotherapy. 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 allowing for combination therapies with immune-checkpoint blockade. Platelet-derived growth factor receptor β (PDGFRβ) is highly expressed in invasive TNBC, both on tumor cells and tumor microenvironment. 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.MethodsThe 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. The anti-proliferative effects of the PDGFRβ aptamer/anti-PD-L1 mAbs combination was assessed in human MDA-MB-231 and murine 4 T1 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 4 T1 xenografts in syngeneic mice were used for dissecting the effect of aptamer/mAb combination on tumor growth, metastasis and lymphocytes infiltration. Ex vivo analyses through immunohistochemistry, RT-qPCR and immunoblotting were performed.ResultsWe 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 mAb-induced cytotoxicity of lymphocytes against tumor cells. Importantly, the aptamer heightens the antibody efficacy in inhibiting tumor growth and lung metastases in mice. It acts on both tumor cells, inhibiting Akt and ERK1/2 signaling pathways, and immune populations, increasing intratumoral CD8 + T cells and reducing FOXP3 + Treg cells.ConclusionCo-treatment of PDGFRβ aptamer with anti-PD-L1 mAbs is a viable strategy, thus providing for the first time an evidence of the efficacy of PDGFRβ/PD-L1 co-targeting combination therapy in TNBC.

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Modern cancer therapy: cryoablation meets immune checkpoint blockade.

Publications

Modern cancer therapy: cryoablation meets immune checkpoint blockade.

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