Association of Siglec-9 positive macrophages with immune checkpoint inhibitor resistance in non-small cell lung cancer

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Objective: Cancer immunotherapy (immune checkpoint inhibitors; ICI therapy) has improved the prognosis of some patients with non-small cell lung cancer (NSCLC). However, many patients develop resistance to ICIs, and there is a need to elucidate the molecular mechanisms underlying this resistance. Various immune checkpoint factors other than programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have been implicated in cancer immune evasion. In particular, some cellular fractions of CD329 (Siglec-9)-positive tissue macrophages (MARCO or SEPP1 positive) have been reported to be involved in ICI reactivity. In this study, we divided NSCLC patients receiving ICI (PD-1 inhibitor) into ICI-sensitive and resistant groups, and aimed to compare and verify the expression of Siglec-9 and other factors in the respective tissue endogenous macrophages.Methods: Tumor tissues were collected from NSCLC patients (n=8) prior to ICI administration, and the expression of Siglec-9, MARCO, and SEPP1 on macrophages isolated from the tumor tissues was analyzed by flow cytometry.Results and Discussion: In the ICI-resistant group (n=3), the percentage of Siglec-9-positive (especially Siglec-9/MARCO-positive) cell groups was increased compared to the ICI-sensitive group (n=5). On the other hand, there was no significant difference in the expression of Siglec-9-positive/SEPP1-positive cell groups.Conclusion: Siglec-9-positive/MARCO-positive macrophages were increased in the group of patients with ICI-resistant NSCLC. This suggests that Siglec-9/MARCO may be a new therapeutic target for ICI resistance.