Wnt/beta-Catenin Signaling and Resistance to Immune Checkpoint Inhibitors: From Non-Small-Cell Lung Cancer to Other Cancers

Lung cancer is the leading cause of cancer-related deaths worldwide. The standard of care for advanced non-small-cell lung cancer (NSCLC) without driver-gene mutations is a combination of an anti-PD-1/PD-L1 antibody and chemotherapy, or an anti-PD-1/PD-L1 antibody and an anti-CTLA-4 antibody with or without chemotherapy. Although there were fewer cases of disease progression in the early stages of combination treatment than with anti-PD-1/PD-L1 antibodies alone, only approximately half of the patients had a long-term response. Therefore, it is necessary to elucidate the mechanisms of resistance to immune checkpoint inhibitors. Recent reports of such mechanisms include reduced cancer-cell immunogenicity, loss of major histocompatibility complex, dysfunctional tumor-intrinsic interferon-gamma signaling, and oncogenic signaling leading to immunoediting. Among these, the Wnt/beta-catenin pathway is a notable potential mechanism of immune escape and resistance to immune checkpoint inhibitors. In this review, we will summarize findings on these resistance mechanisms in NSCLC and other cancers, focusing on Wnt/beta-catenin signaling. First, we will review the molecular biology of Wnt/beta-catenin signaling, then discuss how it can induce immunoediting and resistance to immune checkpoint inhibitors. We will also describe other various mechanisms of immune-checkpoint-inhibitor resistance. Finally, we will propose therapeutic approaches to overcome these mechanisms.

Automated summary

Lung cancer is a major cause of death globally. The standard treatment for advanced non-small-cell lung cancer (NSCLC) without certain gene mutations involves a combination of immunotherapy and chemotherapy or immunotherapy and another type of antibody. Although combination treatment can reduce disease progression, only about half of the patients respond long-term. Therefore, it is important to understand the mechanisms of resistance to immunotherapy. One potential mechanism is the Wnt/beta-catenin signaling pathway. This review summarizes the current knowledge on resistance mechanisms in NSCLC and other cancers, focusing on the role of Wnt/beta-catenin signaling. Therapeutic approaches to overcome these resistance mechanisms are also discussed.