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

Abstract

Aim Tumour budding (‘attacker’) and CD8+ T cells (‘defender’) are recognised as important parameters for risk stratification in colon cancers and, combined, may have an even stronger clinical impact. Here, we determine the value of tumour budding and CD8+ in rectal cancer patients treated with/without neoadjuvant therapy. Methods and results Using digital scans of all tumour slides/case, we analysed CD8+ T cell counts in two patient cohorts: 45 neoadjuvantly treated and 47 primarily surgically treated (totalling n = 543 slides) after double‐staining of the surgical resection specimen for pan‐cytokeratin and CD8+. Tumour buds in hot‐spots were manually counted (area = 0.785 mm2) and CD8+ T cell counts were analysed separately both in tumour budding hot‐spots and the densest CD8+ regions throughout the tumour. In neoadjuvantly treated patients, only tumour budding and not CD8+ T cells was associated with tumour features, including more advanced ypT (P = 0.0062), venous invasion (P = 0.002), lymphatic invasion (P = 0.0003) and perineural invasion (P = 0.0017), as well as higher American Joint Committee on Cancer (AJCC) tumour regression score (P = 0.0035), indicating less tumour response. Overall survival was also worse in patients with high‐grade budding in univariate analysis only. In contrast, all three variables, namely tumour budding (P = 0.0347), CD8+ T cells in budding hot‐spots (P = 0.0382) and CD8+ T cells in the densest areas (P = 0.0117) were also associated with worse (budding) and better (CD8) survival time in the multivariate setting. Conclusion In rectal cancer, tumour budding has clinical relevance in both primarily surgically treated patients and in those with neoadjuvantly treated patients, where it characterises highly aggressive residual disease. CD8+ T cell counts appear not to have prognostic relevance in the neoadjuvant context.

A Novel Combined Tumor Budding-Poorly Differentiated Clusters Grading System Predicts Recurrence and Survival in Stage I-III Colorectal Cancer

“…5 A growing number of studies, however, suggest that TB may retain prognostic significance in the postneoadjuvant setting. [30][31][32] We found TB, PDC, and CS to all be significantly associated with RFS, DSS, and OS in the neoadjuvant treated group, further supporting the prognostic utility of these features in this setting.…”

“…At present, most guidelines do not recommend evaluating TB postneoadjuvant therapy owing to insufficient data supporting its prognostic significance in this setting and concerns regarding the distinction of true TB from treatment effect 5. A growing number of studies, however, suggest that TB may retain prognostic significance in the postneoadjuvant setting 30–32. We found TB, PDC, and CS to all be significantly associated with RFS, DSS, and OS in the neoadjuvant treated group, further supporting the prognostic utility of these features in this setting.…”

Tumor budding and tumor‐infiltrating lymphocytes can predict prognosis in pT1b esophageal squamous cell carcinoma

“…TB and TIL comprise an “attacker‐defender” model, considering that the tumor and tumor microenvironment have been used in other tumors 15 . TB and TIL have been used in combination to predict prognosis of CRC patients with surgery or without adjuvant therapy 4,15 . TIL has been reported to be closely associated with the biological characteristics of ESCC 16 .…”

“…TB and tumor-infiltrating lymphocyte (TIL) have been regarded as an "attacker-defender" model in several tumors. 15 Previous studies have found that ESCC with low TIL exhibits aggressive clinical behavior and is associated with a poor prognosis. 16 In addition, it modifies the effectiveness of TB alone in providing an indication for the prognosis of tumors.…”

The immune microenvironment landscape shows treatment-specific differences in rectal cancer patients

“…The well-established role of CD3+ and CD8+ cells in colorectal cancer (i.e., the immunoscore ( 18 )) has paved the road to investigate the impact of other immune cell subsets. CD11c+ (dendritic cells (DCs)) ( 19 , 20 ), CD20+ (B cells) ( 21 , 22 ), CD3+CD8-FOXP3-(T-helper cells) ( 10 ), CD3+FOXP3+[T-regulatory cells (T-regs)]] ( 23 , 24 ) and CD3+CD8+[cytotoxic T cells (T-cyt)] cells ( 25 , 26 ) have been some of the major targets of immune-profiling in recent years. In newly diagnosed rectal cancers, several studies have elegantly shown an increased presence of T-helper and cytotoxic T cells prior to RCT correlates with better response ( 27 , 28 ) and better recurrence-free survival ( 29 ).…”