Abstract
BackgroundEvidence suggests a confounding effect of mismatch repair (MMR) status on immune response in colorectal cancer. The identification of innate and adaptive immune cells, that can complement the established prognostic effect of CD8 in MMR-proficient colorectal cancers patients, representing 85% of all cases, has not been performed.Methodology/Principal FindingsColorectal cancers from a test (n = 1197) and external validation (n = 209) cohort of MMR-proficient colorectal cancers were mounted onto single and multiple punch tissue microarrays. Immunohistochemical quantification (score 0-3) was performed for CD3, CD4, CD8, CD45RO, CD68, CD163, FoxP3, GranzymeB, iNOS, mast cell tryptase, MUM1, PD1 and TIA-1 tumor-infiltrating (TILs) reactive cells. Coexpression experiments on fresh colorectal cancer specimens using specific cell population markers were performed. In the test group, higher numbers of CD3+ (p<0.001), CD4+ (p = 0.029), CD8+ (p<0.001), CD45RO+ (p = 0.048), FoxP3+ (p<0.001), GranzymeB+ (p<0.001), iNOS+ (p = 0.035), MUM1+ (p = 0.014), PD1+ (p = 0.034) and TIA-1+ TILs (p<0.001) were linked to favourable outcome. Adjusting for age, gender, TNM stage and post-operative therapy, higher CD8+ (p<0.001; HR (95%CI): 0.66 (0.64-0.68)) and TIA-1+ (p<0.001; HR (95%CI): 0.56 (0.5-0.6)) were independent prognostic factors. Moreover, among patients with CD8+ infiltrates, TIA-1 further stratified 355 (35.6%) patients into prognostic subgroups (p<0.001; HR (95%CI): 0.89 (95%CI: 0.8-0.9)). Results were confirmed on the validation cohort (p = 0.006). TIA-1+ cells were mostly CD8+ (57%), but also stained for TCRγδ (22%), CD66b (13%) and only rarely for CD4+, macrophage and NK cell markers.ConclusionsTIA-1 adds prognostic information to TNM stage and adjuvant therapy in MMR-proficient colorectal cancer patients. The prognostic effect of CD8+ TILs is confounded by the presence of TIA-1+ which translates into improved risk stratification for approximately 35% of all patients with MMR-proficient colorectal cancers.
Highlights
The prognosis of patients with colorectal cancer can be viewed as an interaction between tumor- and host-related factors [1]
The prognostic effect of CD8+ tumor infiltrating lymphocytes (TILs) is confounded by the presence of TIA-1+ which translates into improved risk stratification for approximately 35% of all patients with mismatch repair (MMR)-proficient colorectal cancers
This phenotypic constellation, by ‘‘tipping the scale’’ in favour of a strong defence may in part be responsible for the more favourable overall prognosis of patients with MMR-deficient compared to MMR-proficient tumors [9]
Summary
The prognosis of patients with colorectal cancer can be viewed as an interaction between tumor- and host-related factors [1]. The balance between host- and tumorrelated factors is exemplified by mismatch repair (MMR)-deficient sporadic cases, accounting for approximately 15% of all tumors and characterized by defective MMR machinery [6] Patients with these MMR-deficient cancers are described as having abundant CD8+ cytotoxic T-cell infiltrate [7] and are often linked to more ‘‘favourable’’ tumor-related features, namely the presence of a pushing tumor border configuration, the presence of a distinctive band of peritumoral lymphocytic inflammation and little tumor budding, the latter a histomorphological hallmark of epithelial mesenchymal transition [8]. The identification of innate and adaptive immune cells, that can complement the established prognostic effect of CD8 in MMR-proficient colorectal cancers patients, representing 85% of all cases, has not been performed
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