Targeting IL-10R: Enhancing Immune Activation in Cancer

The interleukin-10 receptor (IL-10R) is a key player in regulating immune responses, particularly in suppressing inflammation and maintaining immune tolerance. IL-10R is activated by its ligand, interleukin-10 (IL-10), an anti-inflammatory cytokine that is critical in controlling excessive immune activation and preventing tissue damage during infection or inflammation. However, in the context of cancer, IL-10 signaling can be exploited by tumor cells to suppress immune responses, particularly by inhibiting the activity of T cells and dendritic cells, creating a microenvironment conducive to tumor growth.

Targeting IL-10R with therapies like 1B1.3A, a monoclonal antibody that blocks IL-10 receptor signaling, is a promising strategy in cancer immunotherapy. By inhibiting IL-10R, these therapies aim to remove immune suppression, enhance T cell activation, and improve the immune system’s ability to destroy tumors. This article explores the biological functions of IL-10R, its role in tumor immune evasion, and the therapeutic potential of IL-10R-targeting antibodies in cancer treatment.

IL-10 is a potent anti-inflammatory cytokine produced by various immune cells, including regulatory T cells (Tregs), macrophages, and dendritic cells. Its primary function is to limit excessive immune responses by suppressing the activation and function of effector T cells, NK cells, and antigen-presenting cells (APCs). This is achieved through the engagement of IL-10R, a receptor composed of two subunits: IL-10R1 and IL-10R2.

The downstream effects of IL-10 signaling include:

• Inhibition of pro-inflammatory cytokine production by macrophages and dendritic cells, which reduces immune activation.
• Suppression of T cell proliferation and cytokine production, limiting their ability to attack infected or cancerous cells.
• Promotion of immune tolerance by enhancing Treg activity and inhibiting cytotoxic immune responses.

While IL-10 plays a protective role in preventing autoimmune diseases and excessive inflammation, its immunosuppressive properties are exploited by tumors to create an immune-suppressive microenvironment. Many tumor types, including melanoma, breast cancer, and lung cancer, overproduce IL-10 or upregulate IL-10R on immune cells within the tumor microenvironment. This leads to:

• Suppression of tumor-infiltrating lymphocytes (TILs), particularly CD8+ cytotoxic T cells, which are crucial for targeting and killing tumor cells.
• Inhibition of dendritic cell maturation, preventing effective antigen presentation and T cell activation.
• Promotion of tumor-associated macrophages (TAMs), which further support tumor growth and immune suppression.

Given IL-10R's central role in enabling tumors to evade immune surveillance, blocking this pathway offers a potent strategy to enhance immune activation and boost anti-tumor immunity.