Role of stromal collagen in immunomodulation and prognosis of advanced gastric carcinoma.
Although several hypotheses have been proposed explaining the mechanisms of the immune-privileged status of malignant tumors, the exact pathway is yet to be explored. Tumor stroma plays a vital role in the prognosis of cancer patients; however, the immunomodulatory impact of gastric cancer stroma has not been reported. We have evaluated the amount of stromal collagen and its impact on the infiltration of immune-competent cells into the tumor cell nest in gastric carcinoma. Tissue specimens from 84 advanced gastric carcinoma patients who had undergone a curative resection were evaluated for host immune status (CD8+ T cells), tumor stromal reaction (AZAN staining), tumor Fas ligand expression and incidence of tumor cell apoptosis (by TUNEL). The number of apoptotic tumor cells (apoptotic index [AI]) increased proportionally with an increase in the number of CD8+ T cells within the cancer cell nest (nest CD8) (p = 0.0001). Nest CD8 was inversely correlated with the amount of stromal collagen (p < 0.0001). Nest CD8 and AI became independent predictors of patient survival (p = 0.0023 and p = 0.044, respectively) in Cox's multivariate analysis. The amount of stromal collagen was found to be a significant predictor of disease relapse in univariate analysis (p = 0.0010) but not in multivariate analysis (p = 0.4729). In conclusion, increased nest CD8 produced a survival advantage by inducing tumor cell apoptosis in gastric carcinoma patients. Increased tumor stromal collagen worked as a barrier for CD8+ T-cell infiltration and might be one of the mechanisms of tumor escape from the host immune attack.
Ohno
Satoshi
S
Second Department of Surgery, Shimane Medical University, Shimane, Japan. satoshio@shimane-med.ac.jp
Tachibana
Mitsuo
M
Fujii
Toshiyuki
T
Ueda
Shuhei
S
Kubota
Hirofumi
H
Nagasue
Naofumi
N
D000230:Adenocarcinoma / Q000175:diagnosis / Q000276:immunology* / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003094:Collagen / Q000378:metabolism*; D018572:Disease-Free Survival; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000276:immunology* / Q000628:therapy; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D003094:Collagen