Relationship between immune checkpoint proteins, tumour microenvironment characteristics, and prognosis in primary operable colorectal cancer

Abstract

The tumour microenvironment is an important factor for colorectal cancer prognosis, affecting the patient's immune response. Immune checkpoints, which regulate the immune functions of lymphocytes, may provide prognostic power. This study aimed to investigate the prognostic value of the immune checkpoints TIM‐3, LAG‐3 and PD‐1 in patients with stage I–III colorectal cancer. Immunohistochemistry was employed to detect TIM‐3, LAG‐3, PD‐1 and PD‐L1 in 773 patients with stage I–III colorectal cancer. Immune checkpoint protein expression was assessed in tumour cells using the weighted histoscore, and in immune cells within the stroma using point counting. Scores were analysed for associations with survival and clinical factors. High tumoural LAG‐3 (hazard ratio [HR] 1.45 95% confidence interval [CI] 1.00–2.09, p = 0.049) and PD‐1 (HR 1.34 95% CI 1.00–1.78, p = 0.047) associated with poor survival, whereas high TIM‐3 (HR 0.60 95% CI 0.42–0.84, p = 0.003), LAG‐3 (HR 0.58 95% CI 0.40–0.87, p = 0.006) and PD‐1 (HR 0.65 95% CI 0.49–0.86, p = 0.002) on immune cells within the stroma associated with improved survival, while PD‐L1 in the tumour (p = 0.487) or the immune cells within the stroma (p = 0.298) was not associated with survival. Furthermore, immune cell LAG‐3 was independently associated with survival (p = 0.017). Checkpoint expression scores on stromal immune cells were combined into a Combined Immune Checkpoint Stromal Score (CICSS), where CICSS 3 denoted all high, CICSS 2 denoted any two high, and CICSS 1 denoted other combinations. CICSS 3 was associated with improved patient survival (HR 0.57 95% CI 0.42–0.78, p = 0.001). The results suggest that individual and combined high expression of TIM‐3, LAG‐3, and PD‐1 on stromal immune cells are associated with better colorectal cancer prognosis, suggesting there is added value to investigating multiple immune checkpoints simultaneously.

Update on lymphocyte-activation gene 3 (LAG-3) in cancers: from biological properties to clinical applications

“…For example, one study reported that LAG-3 positivity on TILs in patients with NSCLC was predictive of shorter recurrence-free survival, [49] whereas another study found that LAG-3 on TILs in the intraepithelial and stromal parts of tumors and metastases predicted better disease-specific survival in 553 patients with stage I-IIIB NSCLC [106] . A study in 773 patients with stage I-III colorectal cancer found that high tumor expression of LAG-3 was related to a shorter survival, whereas high LAG-3 on immune cells in the stroma correlated with better survival [107] . Another study found that LAG-3 on TILs was a good prognostic factor in 89 patients who underwent resection for microsatellite instability-high colon cancers, [108] whereas LAG-3 +CD49b+ Tr1 cells were predictive of a poor prognosis and higher LAG-3 mRNA levels predicted advanced stages in colorectal cancer [109,110] .…”

“…[ 106 ] A study in 773 patients with stage I-III colorectal cancer found that high tumor expression of LAG-3 was related to a shorter survival, whereas high LAG-3 on immune cells in the stroma correlated with better survival. [ 107 ] Another study found that LAG-3 on TILs was a good prognostic factor in 89 patients who underwent resection for microsatellite instability-high colon cancers, [ 108 ] whereas LAG-3 +CD49b+ Tr1 cells were predictive of a poor prognosis and higher LAG-3 mRNA levels predicted advanced stages in colorectal cancer. [ 109 , 110 ] An evaluation of the levels of expression of LAG-3 on stromal and intra-epithelial TILs (sTILs or iTILs) in breast cancers found that patients with LAG-3+iTILs had a better prognosis.…”

New Potential Immune Biomarkers in the Era of Precision Medicine: Lights and Shadows in Colorectal Cancer

“…A retrospective analysis was conducted to better identify the prognostic role of LAG3 [ 116 ]. In the 773 stages, I–III CRC patients underwent tumor resection surgery [ 106 ], and the expression of immune checkpoints at the stromal and tumor levels was evaluated by combining immune checkpoint stromal score (CICSS): CICSS 3 (TIM3- LAG3 and PD1 highly expressed), CICSS 2 (only two markers highly expressed), CICSS 1 (one high marker or weakly expressed markers).…”

“…Quantitative analysis of immune checkpoints has been obtained by various methods and scoring systems. It is possible to use a weighted histoscore calculated as: (% unstained tumor cells × 0) + (% weakly stained tumor cells × 1) + (% moderately stained tumor cells × 2) + (% strongly stained tumor cells × 3) to give a range from 0 to 300 [ 116 ].…”

HAMP as a Prognostic Biomarker for Colorectal Cancer Based on Tumor Microenvironment Analysis

“…Given the development of CRC therapy, there are now more choices for primary and metastatic patients; however, there are still some limitations. Increasing evidence has shown that the tumor microenvironment (TME) greatly influences the development of CRC ( 3 ) and that the TME plays an important role in tumor development. The coaction between tumor cells and their supporting cells and changes in metabolism and the immune environment have a close relationship with tumor growth and development ( 4 ).…”