In Situ Cytotoxic and Memory T Cells Predict Outcome in Patients With Early-Stage Colorectal Cancer

• Published in: Journal of clinical oncology Vol. 27; no. 35; pp. 5944 - 5951
• Main Authors: Pagès, Franck, Kirilovsky, Amos, Mlecnik, Bernhard, Asslaber, Martin, Tosolini, Marie, Bindea, Gabriela, Lagorce, Christine, Wind, Philippe, Marliot, Florence, Bruneval, Patrick, Zatloukal, Kurt, Trajanoski, Zlatko, Berger, Anne, Fridman, Wolf-Herman, Galon, Jérôme
• Format: Journal Article
• Language: English
• Published: United States American Society of Clinical Oncology 10-12-2009
• Subjects: Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Colorectal Neoplasms - surgery; Disease-Free Survival; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Immunologic Memory - genetics; Immunophenotyping; Kaplan-Meier Estimate; Leukocyte Common Antigens - analysis; Neoplasm Staging; Proportional Hazards Models; Retrospective Studies; Risk Assessment; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Cytotoxic - immunology; Time Factors; Tissue Array Analysis; Treatment Outcome
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2008.19.6147

Many patients who present with early-stage colorectal cancer (International Union Against Cancer TNM stages I and II) are nevertheless at high risk of relapse. We hypothesized that intratumoral immune reaction could influence their prognosis.
The intratumoral immune reaction was investigated in 29 tumors by large-scale real-time polymerase chain reaction. Cytotoxic (CD8) and memory (CD45RO) T cells were quantified by immunohistochemical analyses of tissue microarrays from the center (CT) and the invasive margin (IM) of the 602 tumors from two independent cohorts. The results were correlated with tumor recurrence and patient survival.
Patients with a strong infiltration of CD45RO(+) cells in the tumor exhibited an increased expression of T-helper 1 and cytotoxicity-related genes. Densities of CD45RO(+) and CD8(+) cells in tumor regions (CT/IM) classified the patients into four distinct prognostic groups based on the presence of high density of each marker in each tumor region. The four groups were associated with dramatic differences in disease-free, disease-specific, and overall survival (all P < .0001). Five years after diagnosis, only 4.8% (95% CI, 0.6% to 8.8%) of patients with high densities of CD8(+) plus CD45RO(+) cells had tumor recurrence, and 86.2% (CI, 79.4% to 93.6%) survived. In contrast, the tumor recurred in 75% (95% CI, 17% to 92.5%) of patients with low densities of these cells, and only 27.5% (95% CI, 10.5% to 72%) survived (all P < .0001). Multivariate analyses showed that the immune criteria had independent effects on the rates of complete remission and survival.
The combined analysis of CD8(+) plus CD45RO(+) cells in specific tumor regions could provide a useful criterion for the prediction of tumor recurrence and survival in patients with early-stage colorectal cancer.