Siglec-7 is a predictive biomarker for the efficacy of cancer vaccination against metastatic colorectal cancer
Kensuke Yamada, Shoichi Hazama, Nobuaki Suzuki, Ming Xu, Yuki Nakagami, Nobuyuki Fujiwara, Ryouichi Tsunedomi, Shin Yoshida, Shinobu Tomochika, Satoshi Matsukuma, Hiroto Matsui, Yukio Tokumitsu, Shinsuke Kanekiyo, Yoshitaro Shindo, Yusaku Watanabe, Michihisa Iida, Shigeru Takeda, Tatsuya Ioka, Tomio Ueno, Hiroyuki Ogihara, Yoshihiko Hamamoto, Yoshinobu Hoshii, Hiroo Kawano, Tomonobu Fujita, Yutaka Kawakami, Hiroaki Nagano
Abstract
Cancer immunotherapy, including vaccination, is considered a major scientific and medical breakthrough. However, cancer immunotherapy does not result in durable objective responses against colorectal cancer (CRC). To improve the efficacy of immunotherapy, the present study investigated several biomarkers for selecting patients who were expected to respond well to immunotherapy. Firstly, a comprehensive proteomic analysis was performed using tumor tissue lysates from patients enrolled in a phase II study, in which five human leukocyte antigen (HLA)‑A*24:02‑restricted peptides were administered. Sialic acid‑binding immunoglobulin type lectin (Siglec)‑7 was identified as a potential predictive biomarker. Subsequently, this biomarker was validated using western blot analysis, and immunofluorescence using tissue samples from the patients enrolled in the phase II study. The expression levels of Siglec‑7 detected by immunofluorescence were quantified and their association with overall survival (OS) in patients treated with the peptide vaccine was examined. Furthermore, considering the important role of tumor‑infiltrating lymphocytes (TILs) for CRC prognosis, the densities of CD3<sup>+</sup>, CD4<sup>+</sup>, CD8<sup>+</sup> and forkhead box P3 (FOXP3)<sup>+</sup> T cells in CRC tissues were examined and compared with Siglec‑7 expression. The mean expression levels of Siglec‑7 were significantly higher in patients with poor prognosis, with an OS of ≤2 years, as shown in comprehensive proteomic analysis (P=0.016) and western blot analysis (P=0.025). Immunofluorescence analysis demonstrated that Siglec‑7 was expressed in intratumoral macrophages. The OS in patients with high Siglec‑7 expression was significantly shorter than in that in patients with low Siglec‑7 expression (P=0.017) in the HLA‑A*24:02‑matched patients. However, this difference was not observed in the HLA‑unmatched patients. There was no significant difference in OS between patients according to the numbers of TILs, nor significant correlation between TILs and Siglec‑7 expression. In conclusion, Siglec‑7 expression in macrophages in tumor tissue may be a novel predictive biomarker for the efficacy of immunotherapy against metastatic CRC.