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en: Immune checkpoint inhibitor-associated paraneoplastic cerebellar degeneration in a case of extensive-stage small-cell lung cancer with pre-existing anti-SOX1 antibody

en: Neurological immune-related adverse events can manifest as paraneoplastic neurological syndrome (PNS), especially in patients with small-cell lung cancer (SCLC). We herein report a 73-year-old man with SCLC treated with an immune checkpoint inhibitor (ICI) combined with chemotherapy. Although the chemo-immunotherapy induced a favorable response to SCLC, he later developed acute cerebellar ataxia. He was diagnosed with paraneoplastic cerebellar degeneration associated with anti-Sry-like high mobility group box 1 (SOX1) autoantibody. The antibody was also identified in serum collected at the diagnosis of SCLC and before ICI administration, which retrospectively suggested that the patient was at risk of ICI-induced PNS. J. Med. Invest. 72 : 172-176, February, 2025.

en: The Journal of Medical Investigation : JMI


en: Hypoxia-inducible factor-targeting therapy augmented the sensitivity to programmed death ligand-1 blockade by enhancing interferon-γ-induced chemokines in tumor cells

en: Immune checkpoint inhibitors (ICIs) targeting programmed death ligand-1 (PD-L1) provide clinical benefits for various advanced malignancies. However, the predictive factors that determine sensitivity to ICIs have not been fully elucidated. We focused on tumor-derived CXCL10/11 as a pivotal factor that determines the response to PD-L1 blockade by regulating T cell accumulation and tumor angiogenesis. We previously reported that CXCL10/11 was upregulated by interferon (IFN)-γ in ICI-sensitive tumor cells but not in ICI-resistant cells, including mouse Lewis lung carcinoma (LLC). In the present study, gene silencing of tumor-derived CXCL10/11 induced resistance to PD-L1 blockade in AB1-HA mesothelioma cell-bearing mice. To identify the mechanisms underlying ICI resistance, we performed a microarray analysis to compare the IFN-γ-inducible genes between ICI-sensitive AB1-HA and ICI-resistant LLC in vitro. A pathway analysis based on microarray data indicated that hypoxia-inducible factor (HIF) 1A is the key signal that inhibits CXCL10/11 expression. We revealed that the HIF1A inhibitors echinomycin (EC) and YC-1 upregulated CXCL10/11 genes induced by IFN-γ in tumor cells in vitro. In addition, combination therapy with PD-L1 blockade and EC demonstrated synergistic antitumor effects in LLC-bearing mice. Combination therapy enhanced tumor infiltration of CD8 T cells and suppressed tumor angiogenesis. The present study suggests that HIF1A signaling in tumor cells dominates ICI resistance via the downregulation of tumor-derived CXCL10/11.

en: International Journal of Cancer

ja: International Journal of Cancer


en: Granulocyte colony-stimulating factor has the potential to attenuate the therapeutic efficacy of chemo-immunotherapy for extensive-stage small-cell lung cancer

en: Granulocyte colony-stimulating factor (G-CSF) has the potential to attenuate the anti-tumor immune responses of T-cells by increasing immune suppressive neutrophils and myeloid-derived suppressor cells. However, the clinical impact of G-CSF on the efficacy of immunotherapy remains unknown. This multi-center retrospective analysis evaluated the impact of G-CSF in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with chemo-immunotherapy. We analyzed 65 patients with ES-SCLC who completed four cycles of induction chemo-immunotherapy and evaluated the effects of G-CSF on progression-free survival (PFS), overall survival (OS), and a durable response to immunotherapy (defined as PFS 12 months). Fifty patients (76.9%) received 1 dose of G-CSF. The PFS of the patients with G-CSF was poorer than that of the patients without G-CSF (median PFS 8.3 vs. 4.9 months, p = 0.009). The OS of the patients with G-CSF tended to be shorter, but not statistically significant, than that of the patients without G-CSF (median OS 24.3 vs. 16.4 months, p = 0.137). In the multivariate analysis, G-CSF administration was associated with poorer PFS (hazard ratio 2.78, 95% CI 1.36-5.69, p = 0.005) and was identified as a determinant of a durable response (odds ratio 0.18, 95% CI 0.04-0.80, p = 0.024). These results were consistent with other definitions of G-CSF administration (administration of 1 dose of pegfilgrastim, or either 5 doses of filgrastim or 1 dose of pegfilgrastim). G-CSF has the potential to attenuate the efficacy of immunotherapy; therefore, the indication for G-CSF during chemo-immunotherapy should be carefully considered for ES-SCLC.

en: International Journal of Clinical Oncology


en: Transformation of epidermal growth factor receptor mutated lung adenocarcinoma to small-cell carcinoma long after the cessation of tyrosine kinase inhibitor treatment: A case series and literature review

en: Respiratory Medicine Case Reports

ja: Respiratory Medicine Case Reports