Histopathological biomarkers of immunotherapy outcome in advanced colorectal cancer: a multicentre retrospective study
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Published on: March 14, 2019
Jianying Chen1, Yanzhi Chen2, Zhigang Chen3
1Department of Histology and Embryology, Jiangxi Medical College, Shangrao, China.
Background:
Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced colorectal cancer (aCRC), but clinical benefit remains largely confined to patients with deficient mismatch repair (dMMR). Responses among patients with proficient mismatch repair (pMMR) are heterogeneous, underscoring the need for accessible biomarkers that can refine patient stratification beyond MMR status. Histopathological features on routine hematoxylin and eosin (H&E)-stained slides may reflect the immune and stromal architecture of the tumor microenvironment. This study investigated the prognostic value and treatment-outcome associations of standardized stromal tumor-infiltrating lymphocytes (sTILs), tumor-stroma ratio (TSR), and tumor budding (TB) in patients with aCRC treated with ICIs.
Methods:
This retrospective multicentre study included 210 patients with pathologically confirmed aCRC who received PD-1/PD-L1-based immunotherapy between January 2021 and June 2025. H&E-stained sections were independently assessed by two blinded pathologists. The primary endpoint was progression-free survival (PFS), with objective response rate (ORR) and overall survival (OS) as secondary endpoints. Survival outcomes were analyzed using Kaplan-Meier estimates and Cox proportional hazards models. Inter-observer agreement was evaluated using Cohen's kappa.
Results:
At a median follow-up of 22.4 months, high sTILs (≥20%) were associated with a significantly higher ORR than low sTILs (47.2% vs. 15.2%, P<0.001). Patients with low stromal content (TSR ≥50%) experienced longer median PFS compared with those with high stromal content (10.8 vs. 5.2 months; HR 0.48, 95% CI 0.35-0.66; P<0.001). Within the pMMR subgroup (n=162), the combination of high sTILs and low TSR identified an immune-active phenotype with an ORR of 38.5% versus 6.1% in patients with neither feature. Multivariable analysis confirmed high sTILs (HR 0.47, 95% CI 0.26-0.84; P = 0.011) and high-grade tumor budding (HR 2.03, 95% CI 1.39-2.96; P<0.001) as independent prognostic factors for PFS, while TSR demonstrated prognostic value in univariate analysis only.
Conclusions:
Standardized assessment of routine H&E-stained histopathological features provides clinically relevant prognostic and outcome-stratifying information in ICI-treated patients in aCRC. These cost-effective biomarkers may complement molecular testing, particularly for stratifying pMMR patients in real-world immunotherapy settings.
Insights
Histopathological features like stromal tumor-infiltrating lymphocytes (sTILs) and tumor-stroma ratio (TSR) can predict treatment response in advanced colorectal cancer (aCRC) patients receiving immune checkpoint inhibitors (ICIs). These H&E-based markers offer valuable prognostic information, especially for proficient mismatch repair (pMMR) tumors.
Area of Science:
- Oncology
- Immunotherapy
- Pathology
Background:
- Immune checkpoint inhibitors (ICIs) have improved advanced colorectal cancer (aCRC) treatment, primarily benefiting patients with deficient mismatch repair (dMMR).
- Patient responses in proficient mismatch repair (pMMR) aCRC are varied, necessitating additional biomarkers for better stratification beyond MMR status.
- Histopathological features on H&E slides may reflect tumor microenvironment characteristics relevant to ICI efficacy.
Purpose of the Study:
- To evaluate the prognostic value of standardized stromal tumor-infiltrating lymphocytes (sTILs), tumor-stroma ratio (TSR), and tumor budding (TB).
- To assess the association of these histopathological features with treatment outcomes in aCRC patients receiving ICIs.
Main Methods:
- Retrospective analysis of 210 aCRC patients treated with PD-1/PD-L1 inhibitors.
- Independent assessment of H&E-stained slides by two pathologists for sTILs, TSR, and TB.
- Survival outcomes (PFS, ORR, OS) analyzed using Kaplan-Meier and Cox models.
Main Results:
- High sTILs (≥20%) correlated with significantly higher objective response rates (ORR) (47.2% vs. 15.2%).
- Low stromal content (TSR ≥50%) was associated with longer progression-free survival (PFS) (10.8 vs. 5.2 months).
- In pMMR patients, high sTILs combined with low TSR identified an immune-active subgroup with higher ORR (38.5% vs. 6.1%). High sTILs and high-grade TB were independent prognostic factors for PFS.
Conclusions:
- Standardized H&E histopathological features provide prognostic and outcome-stratifying information for ICI-treated aCRC patients.
- These cost-effective biomarkers can complement molecular testing for patient stratification, particularly in pMMR subgroups.
- H&E-based features offer valuable insights into the tumor immune microenvironment for real-world immunotherapy settings.