TY - JOUR
T1 - Combined Low Densities of FoxP3+ and CD3+ Tumor-Infiltrating Lymphocytes Identify Stage II Colorectal Cancer at High Risk of Progression
AU - Alleanza contro il Cancro (ACC) Colorectal Cancer Working Group
AU - Cavalleri, Tommaso
AU - Bianchi, Paolo
AU - Basso, Gianluca
AU - Celesti, Giuseppe
AU - Grizzi, Fabio
AU - Bossi, Paola
AU - Greco, Luana
AU - Pitrone, Calogero
AU - Valtorta, Emanuele
AU - Mauri, Gianluca
AU - Truini, Mauro
AU - Dall'Olio, Filippo Gustavo
AU - Brandi, Giovanni
AU - Sartore-Bianchi, Andrea
AU - Ricciardiello, Luigi
AU - Torri, Valter
AU - Rimassa, Lorenza
AU - Siena, Salvatore
AU - Mantovani, Alberto
AU - Malesci, Alberto
AU - Laghi, Luigi
N1 - ©2019 American Association for Cancer Research.
PY - 2019/5
Y1 - 2019/5
N2 - The densities of CD3+ and CD8+ tumor-infiltrating lymphocytes (TILs), combined with tumor-node-metastasis (TNM) staging, have prognostic value for patients with nonmetastatic colorectal cancer. We compared the prognostic value of CD3+ and FoxP3+ TILs at the invasive front, TNM classifiers, and microsatellite (MS) status in a trial set of patients with stage II and III colorectal cancer (n = 413), by recursive partitioning with a classification and regression tree (CART). Significant prognostic factors and interactions were reassessed by logistic regression and Cox proportional-hazards modeling in the trial and a validation set (n = 215) of patients with stage II colorectal cancer. In the trial set, CART indicated that TIL numbers were of value only in predicting recurrence risk for stage II cancers, where low densities of FoxP3+ TILs ranked first and low densities of CD3+ TILs further stratifying risk. Multivariate analysis showed that TILs interacted with tumor stage (FoxP3+, P = 0.06; CD3+, P = 0.02) and MS instability (MSI; FoxP3+; P = 0.02). In stage II MS-stable cancers, concomitant low densities of both FoxP3+ and CD3+ TILs identified patients with the highest progression risk in the trial [HR 7.24; 95% confidence interval (CI), 3.41-15.4; P < 0.001] and the validation (HR 15.16; 95% CI, 3.43-66.9; P < 0.001) sets. FoxP3+ and CD3+ TIL load in colorectal cancer was more informative than other prognostic factors before the cancer progressed to lymph nodes. This prognostic information about TILs, including FoxP3+ cells, suggests that randomized controlled trials might be refined to include interactions between TNM status, molecular classifiers, and postsurgical treatments.
AB - The densities of CD3+ and CD8+ tumor-infiltrating lymphocytes (TILs), combined with tumor-node-metastasis (TNM) staging, have prognostic value for patients with nonmetastatic colorectal cancer. We compared the prognostic value of CD3+ and FoxP3+ TILs at the invasive front, TNM classifiers, and microsatellite (MS) status in a trial set of patients with stage II and III colorectal cancer (n = 413), by recursive partitioning with a classification and regression tree (CART). Significant prognostic factors and interactions were reassessed by logistic regression and Cox proportional-hazards modeling in the trial and a validation set (n = 215) of patients with stage II colorectal cancer. In the trial set, CART indicated that TIL numbers were of value only in predicting recurrence risk for stage II cancers, where low densities of FoxP3+ TILs ranked first and low densities of CD3+ TILs further stratifying risk. Multivariate analysis showed that TILs interacted with tumor stage (FoxP3+, P = 0.06; CD3+, P = 0.02) and MS instability (MSI; FoxP3+; P = 0.02). In stage II MS-stable cancers, concomitant low densities of both FoxP3+ and CD3+ TILs identified patients with the highest progression risk in the trial [HR 7.24; 95% confidence interval (CI), 3.41-15.4; P < 0.001] and the validation (HR 15.16; 95% CI, 3.43-66.9; P < 0.001) sets. FoxP3+ and CD3+ TIL load in colorectal cancer was more informative than other prognostic factors before the cancer progressed to lymph nodes. This prognostic information about TILs, including FoxP3+ cells, suggests that randomized controlled trials might be refined to include interactions between TNM status, molecular classifiers, and postsurgical treatments.
U2 - 10.1158/2326-6066.CIR-18-0661
DO - 10.1158/2326-6066.CIR-18-0661
M3 - Article
C2 - 30804005
VL - 7
SP - 751
EP - 758
JO - Cancer immunology research
JF - Cancer immunology research
SN - 2326-6066
IS - 5
ER -