Immunotherapy of Metastatic Colorectal Cancer: Prevailing Challenges and New Perspectives

Abstract

Patients with recurring or metastatic colorectal cancer (mCRC) have strikingly low long-term survival, while conventional treatments such as chemotherapeutic intervention and radiation therapy marginally improve longevity. Although, many factors involving immunosurveillance and immunosuppression were recently validated as important for patient prognosis and care, a multitude of experimental immunotherapies designed to combat unresectable mCRC have, in few cases, successfully mobilized antitumor immune cells against malignancies, nor conclusively or consistently granted protection, complete remission, and/or stable disease from immunotherapy - of which benefit less than 10% of those receiving therapy. After decades of progress, however, new insights into the mechanisms of immunosuppression, tolerance, and mutation profiling established novel therapies that circumvent these immunological barriers. This review underlines the most exciting methods to date that manipulate immune cells to curb mCRC, including adoptive cell therapy, dendritic cell vaccines, and checkpoint inhibitor antibodies - of which hint at effective and enduring protection against disease progression and undetected micrometastases.

Keywords: Adoptive Immunotherapy; Adoptive T-cell therapy; Allogeneic stem-cell transplant; Antibody therapy; Antitumor immunity; Biomarker; CTLA-4; Cytotoxic T-Lymphocyte; Dendritic cell; Helper T-Cell; Immunosuppression; Immunosurveillance; Immunotherapy; Ipilimumab; Macrophage; Metastatic colorectal cancer; Myeloid-derived suppressor cell; PD-1/L1; Regulatory T-cell; T-cell; Vaccine.

Figure 1. Common immunosuppressive barriers in CRC that are potential targets for immunotherapy

Myeloid-derived suppressor cells (MDSCs, brown) release T_reg (orange) promoting factors, IL-10, TGF-β, and IDO (grey, purple, and blue), and T-cell suppressing arginase and nitric oxide (olive and brown), A. T_regs compete with other T-cells for coreceptor ligation by expressing CTLA-4 and LAG-3. CTLA-4 binds to CD80/CD86 and LAG-3 binds to MHC class II, thereby blocking the transmission of stimulatory signals from DCs (purple) and other antigen-presenting cells (APCs) to effector T-cells, B. T_regs and endogenous lymphocytes serve as sinks and limit the amount of homeostatic cytokines, IL-7 and IL-15 (light blue and red), that are available for effector T-cells, C. Chronic T-cell stimulation through viral challenge and cancer antigens perpetuates PD-1 expression leading to effector T-cell exhaustion, D.

Figure 2. Immunotherapies used to treat metastatic CRC

Immunotherapies designed to direct cytotoxic T-cells to eradicate colorectal tumor cells. Antibody therapy against CRC has two popular targets. Anti-CTLA-4 (purple) liberates CD28 to ligate to CD80/CD86 for CTL (red) activation. Anti-PD-1 (purple) prevents tumor cells (gray) and DCs (violet) from inducing tolerance, unresponsiveness, and exhaustion of T-cell activities. Adoptive cell transfer requires autologous peripheral or sentinel lymph node T-cells (T_H1-cells, blue) to be isolated and propagated in vitro via IL-2 and antigen (red curved bar) stimulation, then delivered back into the patient. Allo-SCT requires donor hematopoietic stem-cells (HSCs, mustard) to be introduced into cancer patients. HSCs mature into lymphoid progenitors (PL, green) and then into functional T-cells (and other lymphocytes) to induce a GvT effect. This effect requires donor CTLs to proliferate in vivo and target malignancies. DC vaccines program the immune system to mount a durable memory response against tumor antigens. DCs are derived ex vivo from peripheral immune cells precursor, then propagated and challenged with tumor antigens. Mature and activated DCs are delivered back into the patient and migrate to the lymph nodes to prime and educate naive T-cells against tumor antigens. In the lymph node, primed T_H1 cells release IFN-γ (dark green) to activate CD8⁺ T-cells. Once mature, CTLs migrate to tumor cells and release cytotoxic mediators (dark red) upon recognition of antigen-MHC complex (light green) on the tumor cell surface.