Peripheral SNCA+ cells as a poor prognostic factor for nivolumab therapy in advanced gastric cancer

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We previously demonstrated that immune cells expressing α-synuclein (SNCA) are dramatically increased in peripheral blood of patients with gastric cancer (GC), but rarely in healthy donors, and that blocking SNCA is significantly effective even in anti-PD1-resistant mouse tumor models with increased SNCA + cells. This suggests that the increased SNCA + cells are involved in resistance to anti-PD1 therapy. However, the relationship between SNCA + cell levels and anti-PD1/PDL1 therapeutic efficacy in GC remains to be determined in clinical settings. In the WJOG10417GTR study, peripheral blood cells collected from advanced GC patients before and one month after nivolumab monotherapy were analyzed for several SNCA + cell populations by flow cytometry, and the relationship between the levels and patient prognosis was statistically analyzed. High levels of SNCA + cells, particularly the myeloid subset, before and after treatment were significantly associated with shorter progression-free survival and overall survival. Patients with low SNCA + cell levels survived for a long time without disease progression, indicating durable responders. These suggest that SNCA + cells are significant poor prognostic factors in nivolumab therapy for advanced GC. Targeting SNCA may be a promising strategy to improve clinical outcomes in anti-PD1/PDL1 therapy for GC.

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