Data from Spatial Context of Immune Checkpoints as Predictors of Overall Survival in Patients with Resectable Colorectal Cancer Independent of Standard Tumor–Node–Metastasis Stages

Although immune checkpoint blockade therapy has shown promising results in a small subset of patients with colorectal cancer with high microsatellite instability, the majority of patients with colorectal cancer do not respond to immune checkpoint blockade therapy. The main obstacle to the success of immunotherapy in cancer treatment is the exhaustion of tumor-infiltrating lymphocytes (TIL). Elucidating the spatial organization of immune checkpoints within the tumor microenvironment (TME) could pave the way for the development of novel prognostic tools and therapeutic strategies to enhance antitumor immune responses. To clarify the spatial and functional diversity of TILs in the colorectal TME, we performed multiplexed IHC to examine the exhaustion of TILs in the TME, the expression of PD-1 and T-cell immunoglobulin and mucin domain–containing protein 3 (TIM-3), which are major biomarkers of T-cell exhaustion, and least absolute shrinkage and selection operator method–Cox analyses of the correlation between colorectal cancer prognosis and TME features. For proof of concept, the antitumor efficacy of TIM-3 and PD-1 dual blockade in colorectal cancer was further evaluated in a CT26 s.c. tumor model of human colorectal cancer. We found that the spatial context of PD-1 and TIM-3 successfully predicted the overall survival of patients with colorectal cancer independent of tumor–node–metastasis stage. Dual targeting of PD-1 and TIM-3 in mouse tumor models inhibited tumor progression and reduced T-cell exhaustion, indicating a potential strategy for improving the clinical treatment of colorectal cancer.

The identification of specific spatial patterns of immune checkpoint expression that correlate with overall survival in patients with colon cancer suggests a potential prognostic tool for risk stratification and treatment selection. These findings pave the way for the development of novel therapeutic strategies to enhance antitumor immune responses.