Oral uracil and tegafur (UFT)/leucovorin (LV) are widely used as a standard adjuvant chemotherapy (CT) for colorectal cancer (CRC). Immunotherapy (IT) such as pembrolizumab are being approved and developed for the treatment of CRC with high microsatellite instability which is specific to right-sided CRC. We previously showed that the increases in the gene expressions of the IT targets, CTLA4 and LAG3, after UFT/LV CT were specific to left-sided CRC (ESMO2017). In this study, we examined the amount of tumor infiltrating lymphocytes (TILs) and the subtype of TILs in tumor tissues after and without UFT/LV CT.
In 90 patients with CRC, UFT (300 mg/m2/day) and LV (75 mg/day) were administered for 2 weeks before surgery (UFT/LV group), and in the other 170 patients with CRC, no CT was treated before surgery (control group). The amounts of TILs were quantitatively evaluated using HE-stained tumor tissue. The subtypes of TILs were evaluated by immunohistochemical analyses (IHA) of the surface markers of lymphocytes (CD3, CD4, CD8 and FoxP3). The patients were divided into low and high groups of the expressions of the markers using the appropriate cutoff values.
The rate of TIL-high patients in UFT/LV group was significantly higher than in control group (34.4% vs. 15.3%, p = 0.0008). In IHA of TILs, the rate of FoxP3-high patients in UFT/LV group was significantly higher than in control group (41.1% vs. 22.4%, p = 0.0024). No differences were observed in other lymphocytic markers, CD3, CD4, and CD8. In left-sided tumors, the rates of TIL- and FoxP3-high patients in UFT/LV group were significantly higher than in control group (45.8% vs. 14.3%, p < 0.0001 and 43.8% vs. 20.9%, p = 0.0060, respectively). In right-sided tumors, there were no differences in both groups.
The increases in TILs, especially FoxP3-positive regulatory T cells, after UFT/LV CT may be specific to left-sided CRC, suggesting that the combination therapy of UFT/LV and immune checkpoint inhibitors or the sequential therapy of immune checkpoint inhibitors followed by UFT/LV can be useful for patients with left-sided CRC.
Clinical trial identification
Legal entity responsible for the study
Sotaro Sadahiro, MD.
Has not received any funding.
H. Nagase: Employee: Taiho Pharmaceutical Co. Ltd. All other authors have declared no conflicts of interest.