A case of discordant histology and expression of programmed death ligand 1 between primary tumor and brain metastases in adenosquamous carcinoma of the lung.

A patient presented with vomiting and gait disturbance. Investigation revealed a single cerebellar tumor and another tumor in the upper lobe of the left lung. Based on the severe vomiting and gait disturbance, we removed the cerebellar tumor first, achieving resolution of symptoms. The cerebellar tumor was pathologically diagnosed as metastatic lung adenocarcinoma. No other metastases were identified, including in the mediastinal lymph nodes. We therefore resected the primary lung tumor. On final pathological analysis, the tumor in the upper lobe of the left lung was diagnosed as adenosquamous carcinoma with no lymph node metastasis. PD-L1 expression was low in the primary lung adenosquamous carcinoma and high in the cerebellar metastasis. Furthermore, both tumors were KRASG12C -positive. Tumor PD-L1 expression is considered important for immune escape. In this case, adenocarcinoma cells in the primary adenosquamous carcinoma may have migrated to form a cerebellar metastasis. In advanced lung cancer, tumor growth may be observed in some lesions even when many other lesions are controlled by chemo- or immunotherapy. Biopsy to confirm histology and PD-L1 expression is worth considering, depending on the location of the metastases and the invasiveness of the biopsy procedure.

Wnt/ß-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-γ signaling, and oncogenic signaling leading to immunoediting. Among these, the Wnt/ß-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/ß-catenin signaling. First, we will review the molecular biology of Wnt/ß-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.