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Combined low-FOXP3+ and -CD3+tumor infiltrating lymphocytes: a signature of stage II MSS colorectal cancer at high-risk of recurrence
  1. Giuseppe Di Caro1,
  2. Giuseppe Celesti1,
  3. Fabio Grizzi1,
  4. Paolo Bianchi1,
  5. Gianluca Basso1,
  6. Federica Marchesi2,
  7. Alberto Mantovani2,
  8. Alberto Malesci3 and
  9. Luigi Laghi1,3
  1. Aff1 grid.417728.f0000000417568807Laboratory of Molecular GastroenterologyHumanitas Clinical and Research Center Milan Italy
  2. Aff2 grid.417728.f0000000417568807Department of Immunology and InflammationHumanitas Clinical and Research Center Milan Italy
  3. Aff3 grid.417728.f0000000417568807Department of GastroenterologyHumanitas Clinical and Research Center Milan Italy

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Meeting abstracts


Low densities of tumor infiltrating lymphocytes (TILs) predict colorectal cancer (CRC) post-surgical recurrence, the likelihood of progression also depending upon tumor stage and microsatellite (MS) status. We benchmarked FoxP3+TIL and CD3+TIL densities as predictor of postsurgical recurrence.


FoxP3+ and CD3+TIL densities were measured as the percentage of immune-reactive area (IRA%) at the tumor invasion front, in a consecutive series of 413 patients (pts) undergone radical surgery for pT3-pT4, stage II (n=211) and III (n=202) CRC, characterized for MS status. Recursive partitioning, as well logistic univariate, interaction, and multivariate analysis were employed for the integrated examination of pathological and immune markers in predicting recurrence.


In a recursive classification tree, nodal status was the main prognostic factor, discriminating higher recurrence rate for stage III (70/202; 34.7%;) than for stage II (32/211, 15.2% P<.001) pts. Within stage II, 0.23%FoxP3+IRA cut-off divided recurrences in 8/127 (6.3%) pts with high (>0.23%) FoxP3+TILs, and in 24/84 (28.6%; P<.001) pts with low (≤0.23%) FoxP3+TILs. Within the latter group, CD3+IRA% further branched recurrences, that occurred in 7/39 (15.2%) pts with IRA>1.86%, but in 17/38 (44.7%; P=.003) pts with less IRA%. Differently, TIL densities did not predict recurrence in stage III. Interaction analysis revealed that the prognostic effects of FoxP3+and CD3+TIL densities were significantly (P<0.05) modified by nodal and MS-status status. ROC curve analysis in stage II pts with MSS CRC confirmed the cut-offs identified by recursive partitioning. At multivariate, low (<0.23%IRA) FoxP3+ and (<1.86% IRA) CD3+TILs were both independent recurrence predictors (O.R, 10.22 and 7.85, respectively; both P<.001), and concomitant low-FoxP3+ and -CD3+TILs conferred the highest recurrence risk (O.R. 12.64; P<.001). Among stage II pts, the low-FoxP3+ and -CD3+TIL signature identified 61% (17/28) of all MSS CRC recurrences, representing 71% (17/24) of post-surgical metastasis (O.R. 18.43; 95%C.I. 6.68-50.86), while none of 58 pts with high-FoxP3+ and -CD3+TIL experienced recurrences.


FoxP3+ and CD3+TIL amount, plus tumor MS status efficiently stratify the risk of relapse of stage II CRCs, and may help in tailoring the post-surgical management of patients.