A combined spatial score of granzyme B and CD68 surpasses CD8 as an independent prognostic factor in TNM stage II colorectal cancer

Abstract

Background Previous assessments of peritumoral inflammatory infiltrate in colorectal cancer (CRC) have focused on the role of CD8 + T lymphocytes. We sought to compare the prognostic value of CD8 with downstream indicators of active immune cell function, specifically granzyme B (GZMB) and CD68 in the tumour microenvironment. Methods Immunohistochemical (IHC) staining was performed for CD8, GZMB, CD68 and CD163 on next-generation tissue microarrays (ngTMAs) in a primary cohort ( n = 107) and a TNM stage II validation cohort ( n = 151). Using digital image analysis, frequency of distinct immune cell types was calculated for tumour proximity (TP) zones with varying radii (10 μm-100 μm) around tumour cells. Results Associations notably of advanced TNM stage were observed for low density of CD8 ( p = 0.002), GZMB ( p < 0.001), CD68 ( p = 0.034) and CD163 ( p = 0.011) in the primary cohort. In the validation cohort only low GZMB ( p = 0.036) was associated with pT4 stage. Survival analysis showed strongest prognostic effects in the TP25μm zone at the tumour centre for CD8 , GZMB and CD68 (all p < 0.001) in the primary cohort and for CD8 ( p = 0.072), GZMB ( p = 0.035) and CD68 ( p = 0.004) in the validation cohort with inferior prognostic effects observed at the tumour invasive margin. In a multivariate survival analysis, joint analysis of GZMB and CD68 was similarly prognostic to CD8 in the primary cohort ( p = 0.007 vs. p = 0.002) and superior to CD8 in the validation cohort ( p = 0.005 vs. p = 0.142). Conclusion Combined high expression of GZMB and CD68 within 25 μm to tumour cells is an independent prognostic factor in CRC and of superior prognostic value to the well-established CD8 in TNM stage II cancers. Thus, assessment of antitumoral effect should consider the quality of immune activation in peritumoral inflammatory cells and their actual proximity to tumour cells. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10048-x.

Granzyme B Expression in the Tumor Microenvironment as a Prognostic Biomarker for Patients with Triple-Negative Breast Cancer

“…Cytotoxic T cells are activated by the transcription factor T-bet, and they release cytokines and cytotoxic agents, such as perforin A and granzyme B (GZMB), that damage target cells and cause apoptosis ( Figure 1 ) [ 5 ]. GZMB is associated with liver cancer progression [ 6 ] and is a potential prognostic marker of colorectal cancer [ 7 ]. Furthermore, serial changes in GZMB expression in non-small-cell lung cancer may serve as a biomarker for monitoring monotherapy with immune checkpoint inhibitors [ 8 , 9 ].…”