The anticancer effects of immune checkpoint inhibitors against CTLA4 and CD274-PDCD1 axes are evident. However, these immunotherapies for colorectal cancers (CRCs) are now limited to a small subset of patients with microsatellite unstable tumors. Thus, therapeutics targeting other types of CRCs is desired. The CD70–CD27 axis plays a co-stimulatory role in promoting the expansion and differentiation of T-lymphocytes through the activation of NFκB pathway. Aberrant activation of the CD70–CD27 axis accelerates tumor cell proliferation, survival, and immune evasion of tumor cells. Based on these observations, drugs modulating the CD70–CD27 axis have been developed with expectation of anticancer effects. In the present study, 269 primary CRCs were evaluated immunohistochemically for CD70, CD27, and FOXP3 expression to assess their clinical usage and the application of CD70–CD27 axis modulating drugs. CRC tumor cells rarely (2.2%) expressed CD70. In contrast, tumor-surrounding fibroblasts showed various CD70 expressions (fCD70) in 14.9%. The logistic regression analysis revealed significant association of fCD70 expression with incomplete resection status (OR, 2.60; 95% CI, 1.10–6.13; P = 0.029). Overall survival was significantly decreased in the cohort of the patients with fCD70-positive tumor (P = 0.0078). Furthermore, significantly more CD27+ tumor-associated lymphocytes were detected within the primary CRCs without metastases (P = 0.024). Thus, the CD70–CD27 axis may have several roles in CRCs independent from their mismatch repair (MMR) system status. CD70–CD27 pathway-modulating therapies may be applied to CRC patients regardless of their tumor MMR status.
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We thank Dr. Yutaka Kondo (Nagoya University) and Dr. Yoshitaka Sekido (Aichi Cancer Center Research Institute) for SW48 and ACC-MESO-1 cells, respectively. We also thank Ms. Kazuko Tanimizu, Mr. Naoki Igari, and Mr. Motoyasu Takeuchi (Aichi Medical University) for their assistance on tissue preparation and immunohistochemical staining. We had the support on the manuscript editing from Ms. Yukiko Kuru (Aichi Medical University).
This work was supported as a part of Grant-in-Aid for Scientific Research (C) (to Shingo Inaguma, 17K08706).
This project was approved by the Institutional Ethical Review Board of Aichi Medical University Hospital.
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Electronic supplementary material
Supplementary Figure S1. Representative images for the measurement of fCD70-positive area. Photographs for fCD70 immunohistochemistry (left) were converted into black and white image (right). Black fCD70-signals were measured by ImageJ software (NIH, Bethesda, MD). This case showed 9,220 pixels, corresponding to 0.415 mm2, of fCD70-positive area. Bar; 1mm. Supplementary Figure S2. Immunoblot analyses of cultured colorectal cancer cells. All of the colon cancer cells expressed CD70 at under detectable levels. In contrast, ACC-MESO-1, a human mesothelioma cell line, expressed CD70. The following siRNAs were synthesized: siControl, 5’-GACGUAUGACUAACUAACATT-3’ and 5’-UGUUAGUUAGUCAUACGUCTT-3’; siCD70, 5’-GCAUCAGCCUGCUGCGUCUTT -3’ and 5’-AGACGCAGCAGGCUGAUGCTT-3’. After 48 hours of siRNA transfection, total lysates were prepared for immunoblot analysis. Anti-CD70 antibody was applied at a dilution of 1:1000. (ZIP 551 kb)
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Inoue, S., Ito, H., Tsunoda, T. et al. CD70 expression in tumor-associated fibroblasts predicts worse survival in colorectal cancer patients. Virchows Arch 475, 425–434 (2019). https://doi.org/10.1007/s00428-019-02565-1
- Colorectal cancer (CRC)