Emerging Immune Checkpoints - ROR1

PD-1 and its ligands PD-L1 and CTLA4 are currently the most commonly used targets for immune checkpoint inhibition. However, emerging checkpoints continue to be discovered, providing additional options for immunotherapy.

Tyrosine kinase-like orphan receptor 1 (ROR1) has gained attention as a potential immune checkpoint. Creative Biolabs describes the emerging role of ROR1 in the immune checkpoint arena and offers services to explore more possibilities.

Introduction to ROR1

ROR1 is a transmembrane protein that has historically been studied in the context of embryonic development. ROR1 is highly expressed in a variety of hematological cancers and solid tumors, and it plays an important role in promoting tumor growth and metastasis, inducing drug resistance in tumor cells, and inhibiting apoptosis. Its renaissance in cancer has piqued the interest of researchers and sparked an exploration of its role as an immune checkpoint.

Fig. 1 ROR1 structure and signaling in cancer.¹

• ROR1 is highly expressed in tumor cells and low in healthy adult tissues, it has become a tumor-specific target.
• Wnt5a is a ligand for ROR1 and increases NF-kB activation in HEK293 cells expressing ROR1.
• In breast cancer cells, ROR1 expression is highly correlated with the EMT gene, and silencing of ROR1 reduces the ability to form metastases.
• In lung adenocarcinoma cell lines, ROR1 phosphorylates c-SRC and amplifies EGF-induced signaling through the variable interaction of FZD with EGFR.

ROR1 in Cancer Immune Evasion

Below are some key aspects of ROR1's involvement in cancer immune evasion.

• Immunosuppression: ROR1 has been observed to interact with the immune system to exert an inhibitory effect on T cells. ROR1 expression on tumor cells is associated with T cell dysfunction, which allows tumors to evade immune surveillance and proliferate.
• Regulation of the tumor microenvironment (TME): ROR1 expression can affect the composition and function of the TME. It promotes an immunosuppressive environment by facilitating Treg and MDSC recruitment.

What about R&D Status?

Due to the low level of ROR1 expression in normal adult tissues and high expression in solid tumors, ROR1 targets have been favored by pharmaceutical companies since 2020, with a variety of therapeutic modalities being developed, including antibody-coupled drugs (ADCs), monoclonal antibodies, bispecific antibodies, and CAR-T therapies, with ADCs being the most promising direction.

The ROR1-ADC class of drugs currently under investigation is mainly targeting hematological and solid tumors.

ROR1 is a very promising and noteworthy target, and its emergence as a potential immune checkpoint opens up new and exciting possibilities in the fight against cancer. At Creative Biolabs, we are at the forefront of these advances, working tirelessly to explore and assay immune checkpoints and to translate this knowledge into innovative therapies.

Reference

1. Borcherding, Nicholas, et al. "ROR1, an embryonic protein with an emerging role in cancer biology." Protein & cell 5.7 (2014): 496-502.

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