Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction.
OBJECTIVE
The prognosis of patients with colorectal cancer has sometimes proved uncertain; thus, the prognostic significance of immune criteria was compared with that of the tumor extension criteria using the American Joint Committee on Cancer/International Union Against Cancer-TNM (AJCC/UICC-TNM) staging system.


METHODS
We studied the intratumoral immune infiltrates in the center of the tumor and in the invasive margin of 599 specimens of stage I to IV colorectal cancers from two independent cohorts. We analyzed these findings in relation to the degree of tumor extension and to the frequency of recurrence.


RESULTS
Growth of the primary tumor and metastatic spread were associated with decreased intratumoral immune T-cell densities. Sixty percent of patients with high densities of CD8(+) cytotoxic T-lymphocyte infiltrate presented with stage Tis/T1 tumor, whereas no patients with low densities presented with such early-stage tumor. In patients who did not relapse, the density of CD8 infiltrates was inversely correlated with T stage. In contrast, in patients whose tumor recurred, the number of CD8 cells was low regardless of the T stage of the tumor. Univariate analysis showed that the immune score was significantly associated with differences in disease-free, disease-specific, and overall survival (hazard ratio [HR], 0.64, 0.60, and 0.70, respectively; P < .005). Time-dependent receiver operating characteristic curve analysis illustrated the predictive accuracy of the immune parameters (c-index = 65.3%, time-dependent c-index [Cτ] = 66.5%). A final stepwise model for Cox multivariate analysis supports the advantage of the immune score (HR, 0.64; P < .001; Cτ = 67.9%) compared with histopathologic features in predicting recurrence as well as survival.


CONCLUSIONS
Assessment of CD8(+) cytotoxic T lymphocytes in combined tumor regions provides an indicator of tumor recurrence beyond that predicted by AJCC/UICC-TNM staging.
INSERM U872, Integrative Cancer Immunology Team, 15 rue de l'Ecole de Médecine, Centre de Recherche des Cordeliers, 75006 Paris, France.
Bernhard
B
Mlecnik
Marie
M
Tosolini
Amos
A
Kirilovsky
Anne
A
Berger
Gabriela
G
Bindea
Tchao
T
Meatchi
Patrick
P
Bruneval
Zlatko
Z
Trajanoski
Wolf-Herman
WH
Fridman
Franck
F
Pagès
Jérôme
J
Galon
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging / Q000379:methods*; D011379:Prognosis; D016016:Proportional Hazards Models; D012372:ROC Curve; D046888:Tissue Array Analysis