Introduction
The recurrence rate after radical esophageal cancer resection is as high as 40-60%, and patients with early recurrence have a poor prognosis. Recently, the indication of immune checkpoint inhibitor (ICI) therapy for esophageal cancer has been expanded to adjuvant therapy based on the results of the CheckMate 577 trial, and its efficacy is expected to increase1. In addition to ICIs, immunotherapies such as cancer peptide vaccines and CAR-T cell therapy are also expected to be applied to esophageal cancer2,3. On the other hand, the response rate of ICI for esophageal cancer is limited to 10-30%4, and the method of selecting patients who will benefit from immunotherapy is controversial.
Aims & Methods
Aims: we expect that elucidating the association between early postoperative recurrence of esophageal cancer and tumor immune microenvironment (TIME) will provide a biomarker for patient selection for immunotherapy, especially for patients who will benefit from immunotherapy in combination with adjuvant chemotherapy.
Methods: 63 patients with pStage II, III, or IV esophageal cancer who underwent radical surgery at our department between May 2014 and June 2020 were included in the study. 63 patients with recurrence within 1 year (ER group n=26) and 63 patients with non-early recurrence (NER group n=37) were retrospectively compared and evaluated for clinicopathological factors including TIME. The results were compared and examined.
Results
Analysis in clinical context: Univariate analysis for early recurrence showed more pStage III/IV in the ER group (RR: 5.04, (95%CI: 1.69-15.0), p<0.01) and more deaths in the ER group than the NER group (RR: 5.69(95%CI: 2.45-13.2), p<0.01).
Analysis of tumor-infiltrating lymphocytes: ROC analysis of CD8-, Foxp3-, TIM3-, and PD1-positive lymphocytes in TIME was performed for early recurrence, with cutoffs set for each, and compared between the two groups. Results showed that CD8, Foxp3, and positive lymphocyte counts were significantly lower in the ER group than the NER group (relative risk: 2.07(95%CI:1.14-3.75), p=0.02,), (relative risk: 2.32(95%CI: 1.36-3.96), p<0.01). Multivariate analysis showed that CD8-positive lymphocyte count was a factor associated with early recurrence (odds ratio=5.17 (95%CI: 1.39-19.3), p=0.01).
Analysis in lymphocyte ratios: Kaplan-Meier curves were generated for Foxp3/CD8, TIM3/CD8, and PD1/CD8 with median cutoff and 1-year RFS between the two groups. 1-year RFS in Foxp3/CD8 tended to be worse in patients with predominant Foxp3 than with inferior Foxp3 (Foxp3/CD8>1.83:73%, Foxp3/CD8<1.83:50%, Log-rank test p=0.08). The 1-year RFS was significantly worse in group A (1-year RFS=A:43%, B:71%, Log-rank test p=0.04). Similarly, for TIM3, when patients with CD8 low and TIM3/CD8 High were analyzed as group A and others as group B, group A had a significantly worse prognosis (1-year RFS=A:45%, B:70%, Log-rank test p=0.05).
Furthermore, PD1 patients with CD8 low and PD1/CD8 high were group A, and all other patients were group B. The prognosis was significantly worse in group A (1-year RFS=A:42%, B:69%, Log-rank test p=0.03).
Conclusion
In addition to CD8 infiltration in TIME, the balance of expression of regulatory lymphocytes was suggested to be involved in early recurrence.
It is suggested that evaluation of TIME aid in patient selection for adjuvant treatment of esophageal cancer.
References
1. Kelly RJ, Ajani JA, Kuzdzal J, et al. N Engl J Med (2021)
2. Nagata Y, Kageyama S, Ishikawa T, et al. cancer Imunol Imunother (2022)
3. Guerra E, Di Pietro R, Basile M, et al. Int J Mol Sci. (2021)
4. Kudo T, Hamamoto Y, Kato K, et al. Lancet Oncol. (2017)
Disclosure
There are no conflicts of interest related to this study.