Tumour budding/T cell infiltrates in colorectal cancer: proposal of a novel combined score

Abstract

Aims The tumour–node–metastasis classification system is used for prognostication purposes and to guide patient management. However, in colorectal cancer (CRC), additional markers are needed to stratify prognostic subgroups. Two promising markers have emerged from large bodies of research: tumour budding and T cell host response (CD3, CD8 and CD45RO infiltrates). However, attempts to combine these two parameters have been sparse. The aim of this study was to perform an assessment of potential protagonists that could be used in a combined score (budding/T cell score, BTS). Methods and results This descriptive, retrospective study was performed on a multipunch tissue microarray containing material from 345 patients with stages I–IV CRC. Areas from tumour centre, front and microenvironment were stained for pancytokeratin/CD3, pancytokeratin/CD8 and pancytokeratin/CD45RO. Tumour buds were scored manually and T cell infiltrates digitally using open‐source software. Tumour buds, T cell counts and combined BTS were associated with clinicopathological features and overall survival (OS). A higher combined BTS score (buds/CD8, tumour centre) performed better than budding or CD8/CD3 alone in predicting nodal metastases (P < 0.0001, OR = 1.466, 95% CI = 1.115–1.928). Only higher BTS (buds/CD3) were significantly associated with poorer OS on multivariate analysis (P = 0.012, hazard ratio = 1.218, 95% confidence interval = 1.044–1.419). Conclusions Although CD8+/CD3+ T cells are predictive of tumour biology in CRC, we found a combined BTS to be stronger in predicting survival and certain features with high clinical relevance, such as nodal metastases, in comparison to budding or T cells alone. Further studies combining T cell infiltrates and tumour budding are necessary to optimise risk assessment of CRC.

Tumour budding and CD8+ T cells: ‘attackers’ and ‘defenders’ in rectal cancer with and without neoadjuvant chemoradiotherapy

“…The Immunoscore Consortium underlines the significant impact of CD8 + T cells within the densest areas in the tumour centre and at the invasion front, focusing upon stages II and III colon cancers only 24 . Previous work from our group and others show that an attacker–defender combined analysis, namely of tumour budding on one hand and CD8 + on the other hand, can modulate survival times and improve the stratification of patients into better or worse prognostic groups 1,6 . Here, we show that low‐grade tumour budding outweighs the importance of CD8 + T cell presence for overall survival but, in contrast, CD8 + T cell counts have a major impact on patient stratification in the high‐grade budding setting.…”

“…investigated budding heterogeneity in multiple blocks/case and found similar results; namely, that heterogeneity in budding counts on cytokeratin staining were low 25 . Secondly, we performed digital image analysis of CD8 + T cell counts, using existing in‐house algorithms 6 . This analysis spared us the extremely laborious task of lymphocyte counting, leading to more precise estimates per case.…”

“…Conversely, the presence of CD8 + T lymphocytes in either the biopsy or surgical resection seems to play a role in modifying the unfavourable prognostic effect of tumour budding alone 6,7 . Our group refers to this as the ‘attacker–defender’ model, which considers both tumour and host immune components 1 .…”

Tumour budding, poorly differentiated clusters, and T-cell response in colorectal cancer

“…Accumulating evidence suggests that adaptive immune response, represented by cytotoxic T cells, plays a crucial role in suppressing tumour invasion and metastasis [6] , and a high density of tumour infiltrating cytotoxic T cells is associated with favourable prognosis in colorectal cancer [7] . A few studies have shown that anti-tumour immune response might restrict tumour budding and indicated that a combined budding-immune cell score might be a stronger predictor of survival than either parameter alone [ 6 , 8 , 9 ]. However, the interplay between anti-tumour immunity and tumour budding/PDCs in the colorectal cancer microenvironment has not been adequately elucidated in terms of specific T-cell subsets driving the associations, as well as tumour molecular features such as microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP) status, long-interspersed nucleotide element-1 (LINE-1) methylation, CTNNB1 (catenin beta 1) and CDH1 (cadherin 1, E-cadherin) expression, and KRAS, BRAF , and PIK3CA mutations.…”

Should a fourth category be added to the international tumor budding consensus conference tumor budding scoring system in colorectal adenocarcinomas?

“…Most studies in the literature draw attention to the association of high tumor budding scores with aggressive tumor characteristics such as advanced pT, pN, AJCC stage, lymphovascular and perineural invasion, distant metastasis, and local tumor recurrence [10,18,[21][22][23][24][25][26]]. Budding's relationship with the histological grade of the tumor is still unclear.…”