Selective serotonin reuptake inhibitors and immune checkpoint blockade in solid tumors: A target trial emulation with pan-cancer transcriptomic analyses
by Po-Huang Chen, Ming-Shen Dai, Mao-Hsuan Huang, Hsin-Yu Chen, Li-Ting Kao, Tina Yi-Jin Hsieh, Hong-Jie Jhou, Cho-Hao Lee Background Preclinical evidence identifies the serotonin transporter (SERT, encoded by SLC6A4) as an immune checkpoint on CD8+ T cells, with selective serotonin reuptake inhibitors (SSRIs) enhancing antitumor immunity in synergy with anti-programmed cell death protein 1…
Selective serotonin reuptake inhibitors (SSRIs) and immune checkpoint blockade have shown promise in treating solid tumors, according to a target trial emulation study. The research, conducted by Po-Huang Chen and colleagues, examined the impact of SSRIs in combination with anti-PD-1 therapy on patients with depression or anxiety receiving immune checkpoint inhibitors (ICIs).
The study, which involved over 187 million patients from the TriNetX federated electronic health record network, found that SSRIs were associated with lower 2-year all-cause mortality compared to benzodiazepines (BZDs). However, SSRI use was also linked to a higher frequency of immune-related adverse events (irAEs), particularly thyroid dysfunction.
The study also found that SLC6A4 expression, which is higher in patients using SSRIs, was inversely correlated with T-cell inflammation in 13 of 20 cancer types. This suggests a potential biological mechanism for the observed benefits of SSRIs in combination with ICIs. The study's limitations include the lack of performance status data and the potential differences between SSRI and BZD users beyond their treatment regimens.
Further research is needed to confirm these findings and explore the potential of SSRIs as an adjuvant to ICIs.
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