Immunotherapy in Colorectal Cancer: Current and Future Strategies

Abstract

Despite the recent advances in the systemic treatment of metastatic colorectal cancer (mCRC), prognostic outcomes have remained to be poor. Thus, what is needed is an innovative treatment approach. Immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) have exhibited a durable response and dominated the treatment of various tumor types. However, in mCRC, the clinical benefit is limited in patients with deficient mismatch repair (dMMR)/high levels of microsatellite instability (MSI-H), comprising approximately 5% of mCRC cases, and some do not respond to ICI treatment. Thus, further research is needed to identify predictive biomarkers. The most urgent need is developing effective immunotherapy for patients with proficient mismatch repair (pMMR)/microsatellite stable (MSS) cancer, which comprises 95% of mCRC cases. Tumors with the pMMR/MSS phenotype often exhibit a lower tumor mutation burden and fewer tumor-infiltrating lymphocytes than dMMR/MSI-H, leading to immune tolerance and evasion in the tumor microenvironment. Therefore, a number of investigative studies aimed at overcoming tumor resistance in current immunotherapy approaches are underway. A better understanding on the complexity and diversity of the immune system's functioning within the tumor microenvironment will increase the potential for developing predictive biomarkers and novel therapeutic strategies to potentiate anti-tumor immunity in patients with mCRC. In this review, we summarize the most recent advances in immunotherapy based on the findings of pivotal clinical trials for patients with mCRC, highlighting potent therapeutic approaches and predictive biomarkers.

Immune Checkpoint Inhibitor Therapy in Colorectal Cancer—The Role of Cellular Pathology

“…Tumors containing a high density of infiltrating lymphocytes (tumor-infiltrating lymphocytes) are associated with better prognosis and an increased chance of response to ICI therapy. 14,33 CRC and other tumors that show dMMR are associated with increased numbers of infiltrating T-cells and improved survival with ICI therapy. 34 The Immunoscore ® (IS) assay for colon cancer comprises measurement of intratumoral and peri-tumoral CD3+ and CD8+ T-cell infiltration in formalin-fixed and paraffin-embedded sections, using IHC and image analysis software.…”

“…For ICI therapy, these biomarkers include surrogate markers of tumor mutational burden (TMB) and the identification of PD-L1 expression by tumor and immune cells (ICs). 14 In a research setting, the assessment of tumor-infiltrating IC density and the recognition of HLA class I expression loss by TCs are also useful predictors of response to ICI therapy. 14,15…”

“…14 In a research setting, the assessment of tumor-infiltrating IC density and the recognition of HLA class I expression loss by TCs are also useful predictors of response to ICI therapy. 14,15…”

“…27 However, not all current guidance requires identification of these markers prior to consideration for ICI therapy—relying instead solely on the identification of dMMR using MMR protein IHC or MSI testing. 14…”

“…ICI therapy has shown very promising results particularly in metastatic CRC, but this benefit is largely limited to tumors that exhibit dMMR. 14 For example, the KEYNOTE-177 phase III trial found that pembrolizumab therapy led to significantly longer progression-free survival than conventional 5-flurouracil-based chemotherapy, when used as first-line treatment for metastatic CRC in patients whose tumors showed dMMR. 12 This benefit is based on the increased immunogenicity of the tumor conferred by the high TMB associated with dMMR status and the increased numbers of tumor-infiltrating lymphocytes within many of these tumors.…”