Chemokines in the Landscape of Cancer Immunotherapy: How They and Their Receptors Can Be Used to Turn Cold Tumors into Hot Ones?

Simple Summary: For the last decade, the most successful approach for treating cancer has been the use of monoclonal antibodies to immune checkpoint inhibitors (ICI), also known as immune checkpoint blockers (ICB). Unfortunately, many cancers do not respond to these treatments. "Hot" tumors are those that show signs of inflammation, meaning they have been invaded by effector T cells rushing to fight the cancerous cells. Evidence suggests that the limited success of ICI-based immunotherapies is related to attempts to treat patients with "cold tumors" that either do not contain effector T cells or in which these cells are markedly suppressed by regulatory T cells (T_regs). Chemokines are a well-defined group of proteins with chemotactic properties. We focus on key chemokines that not only attract leukocytes to tumor sites but also shape their biological properties. We propose using stabilized forms of two of them: CXL9 and CXCL10, to enhance anti-tumor immunity and possibly transform cold tumors into hot ones. Additionally, we discuss the possibility of targeting or deleting a key subset of T_regs that are CCR8⁺ T_regs and are highly dominant at the tumor site of several cold tumors. This may convert these cold tumors into hot tumors, and thus extend the success of immunotherapy beyond its current limits. Over the last decade, monoclonal antibodies to immune checkpoint inhibitors (ICI), also known as immune checkpoint blockers (ICB), have been the most successful approach for cancer therapy. Starting with mAb to cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors in metastatic melanoma and continuing with blockers of the interactions between program cell death 1 (PD-1) and its ligand program cell death ligand 1 (PDL-1) or program cell death ligand 2 (PDL-2), that have been approved for about 20 different indications. Yet for many cancers, ICI shows limited success. Several lines of evidence imply that the limited success in cancer immunotherapy is associated with attempts to treat patients with "cold tumors" that either lack effector T cells, or in which these cells are markedly suppressed by regulatory T cells (T_regs). Chemokines are a well-defined group of proteins that were so named due to their chemotactic properties. The current review focuses on key chemokines that not only attract leukocytes but also shape their biological properties. CXCR3 is a chemokine receptor with 3 ligands. We suggest using Ig-based fusion proteins of two of them: CXL9 and CXCL10, to enhance anti-tumor immunity and perhaps transform cold tumors into hot tumors. Potential differences between CXCL9 and CXCL10 regarding ICI are discussed. We also discuss the possibility of targeting the function or deleting a key subset of T_regs that are CCR8⁺ by monoclonal antibodies to CCR8. These cells are preferentially abundant in several tumors and are likely to be the key drivers in suppressing anti-cancer immune reactivity. [ABSTRACT FROM AUTHOR]