Immunoscore encompassing CD3+ and CD8+ T cell densities in distant metastasis is a robust prognostic marker for advanced colorectal cancer.
BACKGROUND
The immunoscore (IS), an index based on the density of CD3+ and CD8+ tumor-infiltrating lymphocytes (TILs) in the tumor center (CT) and invasive margin (IM), has gained considerable attention as a prognostic marker. Tumor-associated macrophages (TAMs) have also been reported to have prognostic value. However, its clinical significance has not been fully clarified in patients with advanced CRC who present with distant metastases.


METHODS
The density of CD3+, CD4+, CD8+, FOXP3+, CD68+, and CD163+ immune cells within CRC tissue procured from three sites-the primary CT, IM, and distant metastasis (DM)-was determined using immunohistochemistry and digital image analyzer (n=196). The IS was obtained by quantifying the densities of CD3+ and CD8+ TILs in the CT and IM. IS-metastatic and IS-macrophage-additional IS models designed in this study-were obtained by adding the score of CD3 and CD8 in DM and the score of CD163 in primary tumors (CT and IM), respectively, to the IS.


RESULTS
Higher IS, IS-metastatic, and IS-macrophage values were significantly correlated with better prognosis (p=0.020, p≤0.001, and p=0.005, respectively). Multivariate analysis revealed that only IS-metastatic was an independent prognostic marker (p=0.012). No significant correlation was observed between KRAS mutation and three IS models. However, in the subgroup analysis, IS-metastatic showed a prognostic association regardless of the KRAS mutational status.


CONCLUSIONS
IS is a reproducible method for predicting the survival of patients with advanced CRC. Additionally, an IS including the CD3+ and CD8+ TIL densities at DM could be a strong prognostic marker for advanced CRC.
Department of Pathology, Seoul National University Bundang Hospital, Seongnam, South Korea.|Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.
Yoonjin
Y
Kwak
Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.
Jiwon
J
Koh
Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea.
Duck-Woo
DW
Kim
Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea.
Sung-Bum
SB
Kang
Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.
Woo Ho
WH
Kim
Department of Pathology, Seoul National University Bundang Hospital, Seongnam, South Korea.|Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.
Hye Seung
HS
Lee
D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D017252:CD3 Complex / Q000032:analysis*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011956:Receptors, Cell Surface / Q000032:analysis; D015203:Reproducibility of Results; D000098902:CD163 Antigen
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D014408:Biomarkers, Tumor; D000098902:CD163 Antigen; D017252:CD3 Complex; C117307:KRAS protein, human; D011956:Receptors, Cell Surface; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)
colorectal cancer; immunoscore; tumor-associated macrophage; tumor-infiltrating lymphocytes