Computational Image Analysis of T-Cell Infiltrates in Resectable Gastric Cancer: Association with Survival and Molecular Subtypes

Abstract

Background Gastric and gastro-esophageal junction cancers (GCs) frequently recur after resection, but markers to predict recurrence risk are missing. T-cell infiltrates have been validated as prognostic markers in other cancer types, but not in GC because of methodological limitations of past studies. We aimed to define and validate the prognostic role of major T-cell subtypes in GC by objective computational quantification. Methods Surgically resected chemotherapy-naïve GCs were split into discovery (n = 327) and validation (n = 147) cohorts. CD8 (cytotoxic), CD45RO (memory), and FOXP3 (regulatory) T-cell densities were measured through multicolor immunofluorescence and computational image analysis. Cancer-specific survival (CSS) was assessed. All statistical tests were two-sided. Results CD45RO-cell and FOXP3-cell densities statistically significantly predicted CSS in both cohorts. Stage, CD45RO-cell, and FOXP3-cell densities were independent predictors of CSS in multivariable analysis; mismatch repair (MMR) and Epstein–Barr virus (EBV) status were not statistically significant. Combining CD45RO-cell and FOXP3-cell densities into the Stomach Cancer Immune Score showed highly statistically significant (all P ≤ .002) CSS differences (0.9 years median CSS to not reached). T-cell infiltrates were highest in EBV-positive GCs and similar in MMR-deficient and MMR-proficient GCs. Conclusion The validation of CD45RO-cell and FOXP3-cell densities as prognostic markers in GC may guide personalized follow-up or (neo)adjuvant treatment strategies. Only those 20% of GCs with the highest T-cell infiltrates showed particularly good CSS, suggesting that a small subgroup of GCs is highly immunogenic. The potential for T-cell densities to predict immunotherapy responses should be assessed. The association of high FOXP3-cell densities with longer CSS warrants studies into the biology of regulatory T cells in GC.

Association of tumor-infiltrating T lymphocytes with intestinal-type gastric cancer molecular subtypes and outcome

“…One reason may be the relatively small size of distinct subtypes. It should, however, be noted that results regarding this topic are sparse, and the published gastric cancer studies on the correlation between MMR-D tumors and T lymphocyte counts either lack statistical analyses [28], or do not show increased number of T lymphocytes [29]. An exception is the study by Xing et al, which shows an increased number of CD3+ cells but not CD8+ cells in MMR-D tumors as compared with MMR-P tumors [30].…”

Immune cell infiltrates as prognostic biomarkers in pancreatic ductal adenocarcinoma: a systematic review and meta‐analysis

“…Our findings have also suggested an important role for the immune system in PDAC and further research in this area may yield an important therapeutic breakthrough. Advances in multiplex IHC platforms are enabling the analysis of multiple immune markers simultaneously, and have been investigated in pancreatic, gastric and oesophageal cancer [76–79]. Multiplex staining and advanced immunoprofiling enable the investigation of biomarker expression and immune cell infiltration, whilst preserving the special organisation of tumour tissue [80].…”

M1-like TAMs are required for the efficacy of PD-L1/PD-1 blockades in gastric cancer

“…Although unable to prolong the OS of the patients ( Figure 4B, S3B), high CD8 + T cells could significantly improve the DFS ( Figure 4D), as reported in many cancers. 12,13 Then, in the univariate and multivariate Cox regression model of 22 immune cells, M1 among immune cells was an independent favorable prognostic factor in the OS and DFS ( Figure 4E, F, S3C; Table S6-8), and CD8 + T cells were an independent favorable prognostic factor in DFS (figure 4F). To further explore the relationship between M1, CD8 + T cells and TNM stage, the correlation analysis was applied and showed that CD8 + T cells were not related to T, N, M or TNM stage ( Figure 4H, S3E), while M1 was only significantly associated with a lower risk of tumor metastasis ( Figure 4G, S3D).…”