Colorectal Cancer Immunotherapy: State of the Art and Future Directions

Abstract

Cancer immunotherapy has become an indispensable mode of treatment for a multitude of solid tumor cancers. Colorectal cancer (CRC) has been one of the many cancer types to benefit from immunotherapy, especially in advanced disease where standard treatment fails to prevent recurrence or results in poor survival. The efficacy of immunotherapy in CRC has not been without challenge, as early clinical trials observed dismal responses in unselected CRC patients treated with checkpoint inhibitors. Many studies and clinical trials have since refined immunotherapies available for CRC, solidifying immunotherapy as a powerful asset for CRC treatment. This review article examines CRC immunotherapies, from their foundation, through emerging avenues for improvement, to future directions.

Keywords: Cancer Genomics; Colorectal Cancer; Immune Checkpoints; Immunotherapy; Microbiome.

Figure 1

Schematic representation of explored CRC immunotherapy avenues. Immune checkpoint inhibitors (ICIs) are at the center of CRC immunotherapy, while several strategies are combined with ICIs to improve therapy outcome. ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; EGFR, epidermal growth factor receptor; Mφ, macrophage; VEGF, vascular endothelial growth factor. Created with BioRender.com.

Figure 2

Consensus molecular subtype classification in CRC. Consensus molecular subtype (CMS) groups highlight important hallmarks observed in CRC. CMS grouping for CRC has been instrumental as a prognostic marker and predictive indicator for treatment efficacy. CIMP, CpG island methylator phenotype; ECM, extracellular matrix; SCNA, somatic copy number alteration; TGFβ, transforming growth factor beta. Created with BioRender.com.

Figure 3

Impact of tumor genomics on immune responses. Dysfunctional mismatch repair proteins are not able to correct indel mutations, resulting in the production of mutated proteins. These proteins can act as neoantigens for T cell recognition. DNA mutations from dysfunctional mismatch repair proteins can also produce cytoplasmic DNA fragments that can activate the cGAS/STING pathway. The ISGs and chemokines produced then facilitate CD8⁺ T cell recruitment to destroy the tumor. Conversely, the 3 most common mutations in CRC (APC, TP53, KRAS) lead to tumor protection. Mutations derived from these 3 genes lead to the constitutive activation of the WNT/β-catenin pathway. Activation of this pathway upregulates the “do not eat” signal (CD47) and PD-L1. KRAS activation upregulates pro-inflammatory genes to recruit immunosuppressive cells, such as myeloid-derived suppressor cells and regulatory T cells. CCL4, C-C motif chemokine ligand 4; SIRPα, signal regulatory protein alpha; LRP, lipoprotein receptor-related protein; CKIα, casein kinase I alpha; GSK-3β, glycogen synthase kinase 3 beta; TCF/LEF, T cell factor/lymphoid enhancer factor; IRF3, interferon regulatory 3; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells. Created with BioRender.com.