MD Anderson Cancer Center discovered a new approach that enhances immunotherapy in solid tumors

Tumor cells can avoid immune detection and assault via mechanisms such as the production of immunological checkpoint ligands. In addition to PD-1/PD-L1, tumor cells produce CD47, which prevents macrophage engulfment by binding to SIRP on the surface of macrophages and releasing signals that limit macrophage phagocytosis.

Immune checkpoint inhibition therapies, represented by anti-PD-1/PD-L1 and anti-CD47, have shown encouraging results in a variety of tumors. However, one of the reasons for the poor response of solid tumors to immunotherapy compared to hematologic tumors is the relative lack of membrane proteins that promote immune function in solid tumor cells.

SLAMF7 is a self-receptor ligand expressed only in the blood and immune system. SLAMF7 on the surface of blood tumor cells interacts with SLAMF7 on the surface of immune cells such as macrophages, releasing signals that encourage phagocytosis and antigen presentation to tumors by macrophages. Because solid tumor cells lack SLAMF7, macrophages and other antigen-presenting cells are unable to phagocytose and digest them, limiting the killing of solid tumors by subsequent T cells.

Therefore, artificial modification of solid tumor cells to express SLAMF7 to enhance the tumor immunogenicity of solid cells and promote solid tumor sensitivity to immune cells has emerged as a promising immune transformation strategy.

To this end, Wen Jiang at the University of Texas MD Anderson Cancer Center, in collaboration with Betty Y. S. Kim, developed a nano-biocoupling platform for solid tumors in general—bispecific tumor transforming nanoparticles (BiTNs)—based on nano-adjuvant technology. It adds SLAMF7 to the surface of solid tumor cells, thereby promoting macrophage phagocytosis of solid tumor cells and activating the cGAS-STING pathway of phagocytes to sensitize solid tumors to immune checkpoint inhibition therapy. The related results were recently published in the top international journal Nature Nanotechnology.

The BiTNs are designed in a sophisticated way to simultaneously conjugate SLAMF7 protein and antibodies targeting solid tumor cells on nanoparticle carriers, which firmly bind solid tumor cells through antibodies, thereby indirectly immobilizing SLAMF7 protein on the cell surface and activating phagocytosis of tumor cells by macrophages.

The researchers first examined the immunoconverting ability of BiTNs on HER2-positive breast cancer cells. At this point, the BiTNs were called BiTNHER because the conjugated antibody was a HER2 antibody.

In vitro, macrophages were co-cultured with breast cancer cells, and the addition of BiTNHER boosted phagocytosis of HER2-positive breast cancer cells while having no effect on phagocytosis of HER2-negative breast cancer cells, demonstrating BiTNHER's high targeting. In contrast, phagocytosis of HER2-positive breast cancer cells by macrophages was reduced with the addition of SLAMF7 antibody or SLAMF7 knockdown in macrophages, suggesting that BiTNHER transformed HER2-positive breast cancer cells to SLAMF7-positive and triggered phagocytosis by macrophages.

Because antibodies can cause antibody-dependent cytophagocytosis by attaching to macrophage Fc receptors via their own Fc fragments. To rule out the role of the HER2 antibody Fc fragment in the macrophage-promoting effect of BiTNHER, researchers knocked it down and discovered that macrophages showed strong and specific phagocytosis of HER2-positive breast cancer cells despite having a slightly reduced phagocytic capacity, demonstrating that the pro-phagocytic effect of BiTNs is primarily mediated through the SLAMF7-SLAMF7 pathway.

BiTNHER itself can induce moderate phagocytosis of macrophages, but when combined with CD47 antibody, it not only increases the phagocytosis of HER2-positive breast cancer cells, but also induces higher levels of antigen presentation, T cell activation, and proliferation.

In vitro tests indicated that the combination of BiTNHER and anti-CD47 therapy was effective in initiating a tumor immune response. The researchers next examined BiTNHER's anti-tumor capabilities in vivo using animal models.

In HER2-positive breast cancer mice, the combination of BiTNHER and anti-CD47 treatment significantly slowed tumor development, decreased tumor burden, and lengthened longevity compared to HER2-negative breast cancer mice with BiTNHER or anti-CD47 monotherapy.

After combination therapy, researchers analyzed immune cells infiltrating the tumor and found enhanced macrophage activity, increased numbers of NK and DC cells, increased T cells, especially CD8+ effector T cells, and decreased Treg cells, which suppress immunity. These results suggest that BiTNs enhance the clearance of tumor cells by immunotherapy by promoting macrophage phagocytosis and bridging innate and adaptive immunity.

In addition, the researchers found that peripheral blood IL-2 and IFN-γ levels increased in the combination-treated mice, naïve T cells decreased in the spleen, and splenocytes converted to a memory T cell phenotype, suggesting that BiTNs activate systemic immunity. There was no significant difference in blood cell counts in mice before and after treatment, and only a slight increase in lymphocytes, supporting the safety of BiTNs treatment.

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