CD3+ cells at the invasive margin of deeply invading (pT3–T4) colorectal cancer and risk of post-surgical metastasis: a longitudinal study

Laghi, Luigi; Bianchi, Paolo; Miranda, Elena; Balladore, Emanuela; Pacetti, Veronica; Grizzi, Fabio; Allavena, Paola; Torri, Valter; Repici, Alessandro; Santoro, Armando; Mantovani, Alberto; Roncalli, Massimo; Malesci, Alberto

doi:10.1016/s1470-2045(09)70186-x

Cited by 216 publications

(224 citation statements)

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“…A prognostic marker indicating risk of recurrence and cancer-related death is of particular clinical interest in stage II colorectal cancer, since high-risk patients within this subgroup may potentially benefit from adjuvant chemotherapy, which today is not routinely administered. Together with other stage-stratified results, 21,24,40,41,47,55,58 Figure 2 Cancer-specific survival in colorectal cancer patients with low (3-4), intermediate (5)(6), and high (7-12) total CD3 score (log rank Po0.0001). our findings justify the use of tumor infiltrating T cells as a prognostic marker in stage II colorectal cancer.…”

Section: Discussionsupporting

confidence: 52%

“…[24][25][26][27][28][29][30][31][32][33] As in this study, MSI tumors have previously been reported to have a higher degree of T-cell infiltration than MSS tumors. [35][36][37] Yet the potential confounding effect of MSI screening status on the prognostic importance of T-cell infiltration has been considered in only a minority of reports, of which most, 32,36,[39][40][41]46,53,54 but not all, 30,55 found that the better prognosis associated with dense T-cell infiltration was independent of MSI screening status. In this study, a better prognosis was seen in patients with MSS tumors densely infiltrated by T cells compared with poorly or intermediately infiltrated MSI tumors, whereas MSI screening status was not significantly related to prognosis in subgroups of highly and poorly infiltrated tumors separately.…”

Section: Discussionmentioning

confidence: 99%

“…34 CIMP-high and MSI tumors are frequently infiltrated by a large number of T cells. 4,[35][36][37][38] However, few large studies of tumor infiltrating T cells and colorectal cancer patient survival have taken into account the potentially confounding effect of MSI screening status, 30,32,[39][40][41][42] and only one other research group has considered CIMP. 32,42 Furthermore, T-cell infiltration can be assessed in various locations within the tumor, such as the tumor front, tumor center, and the intraepithelial compartment, but few studies have evaluated these separately.…”

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confidence: 99%

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Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor

et al. 2011

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The aim of this study was to relate the density of tumor infiltrating T cells to cancer-specific survival in colorectal cancer, taking into consideration the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) screening status. The T-cell marker CD3 was stained by immunohistochemistry in 484 archival tumor tissue samples. T-cell density was semiquantitatively estimated and scored 1-4 in the tumor front and center (T cells in stroma), and intraepithelially (T cells infiltrating tumor cell nests). Total CD3 score was calculated as the sum of the three CD3 scores (range 3-12). MSI screening status was assessed by immunohistochemistry. CIMP status was determined by quantitative real-time PCR (MethyLight) using an eightgene panel. We found that patients whose tumors were highly infiltrated by T cells (total CD3 score Z7) had longer survival compared with patients with poorly infiltrated tumors (total CD3 score r4). This finding was statistically significant in multivariate analyses (multivariate hazard ratio, 0.57; 95% confidence interval, 0.31-1.00). Importantly, the finding was consistent in rectal cancer patients treated with preoperative radiotherapy. Although microsatellite unstable tumor patients are generally considered to have better prognosis, we found no difference in survival between microsatellite unstable and microsatellite stable (MSS) colorectal cancer patients with similar total CD3 scores. Patients with MSS tumors highly infiltrated by T cells had better prognosis compared with intermediately or poorly infiltrated microsatellite unstable tumors (log rank P ¼ 0.013). Regarding CIMP status, CIMP-low was associated with particularly poor prognosis in patients with poorly infiltrated tumors (multivariate hazard ratio for CIMP-low versus CIMP-negative, 3.07; 95% confidence interval, 1.53-6.15). However, some subset analyses suffered from low power and are in need of confirmation by independent studies. In conclusion, patients whose tumors are highly infiltrated by T cells have a beneficial prognosis, regardless of MSI, whereas the role of CIMP status in this context is less clear.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor

et al. 2011

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“…In some experiments, the anti-tumor effect could be credited to the recruitment of T cells at the tumor site. In diverse human tumors, especially in colorectal cancer, an abundance of TIL is a strong prognostic factor and active research is focusing on the chemokines responsible for their recruitment [46,47]. TIL have been reported to express the CXCR3 receptor; the corresponding ligands CXCL9 and CXCL10 can elicit anti-tumoral responses which correlated with increased infiltration of CD4 and CD8 lymphocytes [48].…”

Section: Chemokine Regulation Of Leukocyte Attraction Within Tumorsmentioning

confidence: 99%

Chemokines in cancer related inflammation

Allavena

Germano

Marchesi

et al. 2011

Experimental Cell Research

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Chemokines are key players of the cancer-related inflammation. Chemokine ligands and receptors are downstream of genetic events that cause neoplastic transformation and are abundantly expressed in chronic inflammatory conditions which predispose to cancer. Components of the chemokine system affect multiple pathways of tumor progression including: leukocyte recruitment, neo-angiogenesis, tumor cell proliferation and survival, invasion and metastasis.Evidence in pre-clinical and clinical settings suggests that the chemokine system represents a valuable target for the development of innovative therapeutic strategies

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“…They showed that the expression of the T-box transcription factor eomesodermin, which is critically involved in controlling cytolytic activity of CD8+ T cells, inversely correlates to the occurrence of lymph node metastasis in CRC patients [46]. In contrast, Laghi et al [47] found that the density of CD3 + cells in the invasive margin of CRC could not be used as an independent predictor of survival, and at least for now, the TNM classification should remain the preferred prognostic system.…”

Section: Gene Expression Profiling and In Situ Ihcmentioning

confidence: 99%

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

Deschoolmeester

Baay

Lardon

et al. 2011

Cancer Microenvironment

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There is growing evidence that both local and systemic inflammatory responses play an important role in the progression of a variety of solid tumors. Colorectal cancer (CRC) results from the cumulative effect of sequential genetic alterations, leading to the expression of tumor-associated antigens possibly inducing a cellular antitumor immune response. It is well recognized that cytotoxic lymphocytes (CTLs) constitute one of the most important effector mechanisms of anti-tumor-immunity. However, their potential prognostic influence in CRC remains controversial. In addition, other key players like natural killer cells, tumor associated macrophages and regulatory T cells play an important role in the immune attack against CRC and need further investigation. This review will mainly focus on the role of the adaptive immune system in CRC and particularly in regard to microsatellite instability.

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CD3+ cells at the invasive margin of deeply invading (pT3–T4) colorectal cancer and risk of post-surgical metastasis: a longitudinal study

Cited by 216 publications

References 21 publications

Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor

Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor

Chemokines in cancer related inflammation

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

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