S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Medicine (의학과) Theses (Ph.D. / Sc.D._의학과)
The prognostic implications of tumor infiltrating immune cells and PD-L1 expression in microsatellite-unstable advanced gastric cancers
현미부수체불안정성 진행성위암에서 종양침윤면역세포와 PD-L1의 발현이 갖는 예후적 가치
- 의과대학 의학과
- Issue Date
- 서울대학교 대학원
- stomach neoplasm; microsatellite instability; tumor infiltrating lymphocytes; tumor associated macrophages; Programmed death ligand-1
- 학위논문 (박사)-- 서울대학교 대학원 의과대학 의학과, 2017. 8. 강경훈.
- Microsatellite instability-high (MSI-H) gastric cancers are highly immunogenic due to the accumulation of neo-antigens which are produced as a result of frameshift mutation in mismatch-repair-deficient condition. Immunoscore was demonstrated as a powerful prognostic indicator and might be equivalent to the AJCC/UICC-TNM staging system in predicting patients’ clinical outcome in malignant tumors. Programmed death ligand-1 (PD-L1) expression was shown to be significantly associated with MSI-H phenotype and high density of tumor infiltrating lymphocytes (TILs) and tumor associated macrophages (TAMs). In this study, we tried to figure out the efficacy of immunoscore for predicting patients’ outcome and how they linked to the TAM and expression status of PD-L1 in tumor cells and immune cells in MSI-high gastric cancers. In 153 patients who were diagnosed as MSI-H advanced gastric cancer, CD3+ TILs, CD8+ TILs and CD68+ TAMs, CD163+ TAMs were analyzed by computerized image analysis system in four different areas (epithelial and stromal compartments of both tumor center and invasive front). The median value of the specific TIL and TAM density was used as the cut-off level to separate the low and high densities of the TILs and TAMs in each area. The immunoscore(I) was quantified by the number of high densities of CD3+ and CD8+ TIL in both regions and compartments (TC and IF within Epithelial and Stromal compartments), ranging from I0 to I8. Each TAM score was determined by adding the number of high densities of CD68+ or CD163+ TAM in both regions and compartments, ranging from score 0 to score 4. Using immunohistochemistry, the expression of PD-L1 was also analyzed in tumor cells (T-PD-L1) and immune cells (I-PD-L1). We found that there was a positive correlation between TILs and TAMs densities in epithelial and stromal compartments. We figure out that high immnoscore was correlated with prolonged overall and disease free survival and high immunoscore in both E and S compartments was an independent good prognostic indicator. Compared with negative expression of T-PD-L1 and I-PD-L1, the positive expression of T-PD-L1 and I-PD-L1 was significantly associated with higher immunoscore and TAM score, except for the correlation between T-PD-L1 and CD163+ TAM score. A combined survival analysis of PD-L1 expression and immunoscore revealed 4 distinct subgroups with statistically significant difference for overall survival. That is, T-PD-L1 (+)/immunoscoreLow group showed the worst, and T-PD-L1 (+)/immunoscoreHigh group showed the best prognosis. There was no significant prognostic difference according to CD68+ TAM score. However, the patients with low density of CD163+ TAM (score 0) was significantly correlated with poor survival outcome compared with those with high density of CD163+ TAM (score 1-4). In conclusion, our study revealed that the immunoscore using CD3+ and CD8+ T lymphocytes subpopulation is a reliable methodology to predict the clinical outcome of MIS-H GC patients and high immunoscore is positively correlated with PD-L1 expression in tumor cells and immune cells in MSI-H GCs. We also demonstrated that PD-L1 expression is mainly induced by adaptive immune resistant mechanism in MSI-H GCs. Furthermore, immunoscore can be a relevant regulator in determining the prognostic role of PD-L1 expression in MSI-H GCs. Although, the prognostic role of TAM was not entirely elucidated, TILs and TAMs are considered to be influenced by each other and the prognostic effect can be determined in proportional balance of both TAMs and TILs in MSI-H GCs.