Harnessing Myeloid Cell Cytotoxicity through Engineered Fc Receptor Signaling for Tumor Immunotherapy

Core Concepts

Activation of IgM receptor signaling in myeloid cells induces massive tumor cell killing through secretion of lytic granules and reactive oxygen species. Overcoming the challenge of expressing antibody-derived tumor antigen recognition domains in myeloid cells, a novel chimeric Fc receptor design enables antigen-specific tumor cell lysis by myeloid cells.

Abstract

The content explores strategies to harness the cytotoxic potential of myeloid cells for cancer immunotherapy. Key highlights:

Myeloid cells, unlike T cells, are well-adapted to the harsh tumor microenvironment and can produce cytotoxic compounds, but often adopt an immunosuppressive phenotype.

Activation of IgM receptor signaling in myeloid cells induces secretion of lytic granules and reactive oxygen species, leading to massive tumor cell death. However, myeloid cells are unable to ectopically express antibody-derived tumor antigen recognition domains (scFv) due to an ER stress response.

To overcome this limitation, the authors designed a chimeric Fc receptor that fuses the high-affinity FcγRI for IgG recognition with IgM receptor-driven signaling. This construct enables myeloid cells to mediate antibody-dependent tumor cell killing.

In vitro experiments demonstrate that myeloid cells expressing the modified Fc receptor, when incubated with tumor-binding IgG antibodies, induce polarized secretion of Granzyme B and reactive oxygen species, leading to significant tumor cell lysis.

In vivo, mRNA-engineered myeloid cells expressing the modified Fc receptor, combined with tumor-targeting antibodies, inhibit tumor growth and increase T cell infiltration into the tumor.

The work highlights the challenges in genetically reprogramming myeloid cells and provides a framework for endowing them with antigen-specific cytotoxicity, harnessing their capacity to migrate and survive in the harsh tumor microenvironment.

Stats

Incubation of myeloid cells with IgG-coated tumor cells induced higher levels of Granzyme B and nitric oxide compared to IgM-coated tumor cells.
Activation of myeloid cells with IgG-coated tumor cells led to stronger phosphorylation of MAP kinase enzymes compared to IgM-coated tumor cells.
Myeloid cells expressing the modified Fc receptor, when incubated with tumor-binding IgG antibodies, showed significantly higher tumor cell lysis compared to myeloid cells alone.
In vivo, mRNA-engineered myeloid cells expressing the modified Fc receptor, combined with tumor-targeting antibodies, inhibited tumor growth and increased T cell infiltration into the tumor.

Quotes

"Activation of the IgM receptor signaling in myeloid cells induces massive killing of tumor cells."
"To overcome this limitation, we designed chimeric receptors that are based on the high-affinity FcγRI for IgG."
"Incubation of macrophages expressing these receptors along with tumor-binding IgG induced massive tumor cell killing and secretion of reactive oxygen species and Granzyme B."

Key Insights Distilled From

Expression of modified FcγRI enables myeloid cells to elicit robust tumor-specific cytotoxicity

by Carmi,Y., Fa... at www.biorxiv.org 10-02-2023

https://www.biorxiv.org/content/10.1101/2023.09.30.560338v3

Deeper Inquiries

How could the modified Fc receptor design be further optimized to enhance myeloid cell cytotoxicity against tumors?

The modified Fc receptor design can be further optimized in several ways to enhance myeloid cell cytotoxicity against tumors. One approach could involve fine-tuning the signaling cascades activated by the chimeric receptor. By understanding the specific downstream pathways that lead to cytotoxicity, researchers can optimize the design to maximize the killing potential of myeloid cells. Additionally, optimizing the affinity of the chimeric receptor for tumor antigens can improve the specificity and efficacy of tumor cell killing. This can be achieved through protein engineering techniques to enhance the binding affinity of the receptor for tumor antigens.
Furthermore, incorporating additional co-stimulatory molecules or immune checkpoint inhibitors into the chimeric receptor design can enhance the activation and function of myeloid cells. By providing additional signals that promote cytotoxicity and immune activation, the modified Fc receptor design can be optimized to elicit a more robust anti-tumor response. Additionally, optimizing the delivery method of the modified receptors, such as using viral vectors or nanoparticles, can improve the efficiency of transfection and expression in myeloid cells, further enhancing their cytotoxic potential against tumors.

What are the potential limitations or side effects of using antibody-dependent myeloid cell activation for cancer immunotherapy?

While antibody-dependent myeloid cell activation shows promise for cancer immunotherapy, there are potential limitations and side effects that need to be considered. One limitation is the potential for off-target effects, where the activated myeloid cells may target healthy tissues or cells expressing low levels of the target antigen. This can lead to unintended tissue damage and toxicity, impacting the overall safety of the treatment. Additionally, the immune response generated by myeloid cell activation may not be specific enough to completely eradicate tumors, leading to incomplete tumor clearance and potential relapse.
Another limitation is the potential for immune evasion by tumors, where they may downregulate the target antigen or develop resistance to the activated myeloid cells. This can reduce the effectiveness of the treatment and limit its long-term benefits. Furthermore, the complexity of the tumor microenvironment, including immunosuppressive factors and inhibitory pathways, can hinder the activation and function of myeloid cells, reducing their cytotoxic potential against tumors.
Side effects of antibody-dependent myeloid cell activation may include systemic inflammation, cytokine release syndrome, and autoimmune reactions. The activation of myeloid cells can lead to the release of pro-inflammatory cytokines and chemokines, causing systemic inflammation and potentially severe side effects. Additionally, the immune response generated by myeloid cell activation may inadvertently target healthy tissues, leading to autoimmune reactions and adverse events.

What other signaling pathways or immune receptors could be leveraged to reprogram myeloid cells and harness their cytotoxic potential against cancer?

In addition to the Fc receptor design discussed in the context, there are several other signaling pathways and immune receptors that could be leveraged to reprogram myeloid cells and harness their cytotoxic potential against cancer. One potential pathway is the STING (Stimulator of Interferon Genes) pathway, which plays a crucial role in activating the innate immune response against tumors. By activating the STING pathway in myeloid cells, it can enhance their anti-tumor activity and promote the release of pro-inflammatory cytokines and chemokines.
Another immune receptor that could be leveraged is the NKG2D receptor, which is expressed on natural killer cells and some myeloid cells. By engineering myeloid cells to express NKG2D receptors, they can recognize stress-induced ligands on tumor cells and induce cytotoxicity. This approach can enhance the tumor-killing capacity of myeloid cells and improve their anti-tumor immune response.
Furthermore, targeting immune checkpoint receptors, such as PD-1 or CTLA-4, on myeloid cells can reprogram their immunosuppressive phenotype and enhance their cytotoxic potential against tumors. By blocking these inhibitory pathways, myeloid cells can be activated to mount a more robust anti-tumor immune response and improve the efficacy of cancer immunotherapy. Additionally, modulating the NF-κB signaling pathway or the JAK-STAT pathway in myeloid cells can also enhance their cytotoxic potential and promote tumor cell killing.