Immunotherapy for Colorectal Cancer: Mechanisms and Predictive Biomarkers

Abstract

Though early-stage colorectal cancer has a high 5 year survival rate of 65-92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical and clinical investigations of immunotherapy for treatment of colorectal cancer including immune checkpoint blockade, adoptive cell therapy, monoclonal antibodies, oncolytic viruses, anti-cancer vaccines, and immune system modulators have been promising, but demonstrate limitations for patients with proficient mismatch repair enzymes. In this review, we discuss preclinical and clinical studies investigating immunotherapy for treatment of colorectal cancer and predictive biomarkers for response to these treatments. We also consider open questions including optimal combination treatments to maximize efficacy, minimize toxicity, and prevent acquired resistance and approaches to sensitize mismatch repair-proficient patients to immunotherapy.

Keywords: NK cell; T cell; adoptive cell therapy; anti-cancer vaccines; checkpoint blockade; colorectal cancer; cytokine; immunotherapy; monoclonal antibodies; oncolytic viruses.

Figure 1

Immune cell and cancer cell interactions relevant to ICB therapy. CD8+ T cells, CD4+ T cells, NK cells, and T regs express receptors that are susceptible to binding by various cognate ligands present on the surface of colorectal cancer cells or APCs. Ligand binding results in immunosuppressive, or immunostimulatory in the case of NKG2D, signaling. ICB is a therapeutic approach involving inhibition of various receptor–ligand interactions. APC, antigen-presenting cell; ICB, immune checkpoint blockade; NK cell, natural killer cell. Created in BioRender.

Figure 2

Engineered TCR therapy vs. CAR-T cell therapy. Engineered TCR T cell therapy involves engineering T cells with receptors that are specific for MHC class I-presented antigenic peptides. CAR-T cell therapy involves direct recognition of CAAs on the cancer cell surface. CAA, cancer-associated antigen; CAR, chimeric antigen receptor; MHCI, major histocompatibility complex class I; TCR, T cell receptor. Created in BioRender.

Figure 3

Key biomarkers of response to IT in CRC. (1) Certain genetic alterations in CRC cells have been associated with better response to IT. (2) A high level of ctDNA correlates with worse response to many cancer therapies including IT. (3) Neoantigen load is a key biomarker of response to several ITs including ICB. (4) High antigen presentation efficiency is associated with better response to T cell-based ITs. (5) Diversity of the TCR repertoire is associated with better response to IT. (6) A high level of CD8+ T cell activation is associated with better response to different ITs. (7) Levels of circulating and tumor-infiltrating immune cells including immune stimulatory cells (such as T cells and NK cells) and immune suppressor cells (such as T regs, MDSCs, and M2 macrophages), predict response to many types of IT. (8) Expression of inhibitory and activating receptors is impacts response to many types of IT, especially ICB. Circulating exosomes containing soluble receptors may also have predictive value. (9) Expression of pro- and anti-tumor cytokines by cancer cells and immune cells plays a role in response to all ITs. (10) Levels of certain gut microbes in the tumor, and levels of circulating microbe-associated compounds, may predict response to IT. APC, antigen-presenting cell; CRC, colorectal cancer; ctDNA, circulating tumor DNA; ICB, immune checkpoint blockade; IT, immunotherapy; MDSC, myeloid-derived suppressor cell; NK, natural killer; TCR. T cell receptor; T reg, T regulatory cell.