Neoadjuvant Immunotherapy for Patients with dMMR/MSI-High Gastrointestinal Cancers: A Changing Paradigm

Abstract

Immune checkpoint inhibitors have revolutionized the management of mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) gastrointestinal cancers, particularly colorectal cancer. Cancers with the MMR-D/MSI-H genotype often carry a higher tumor mutation burden with frameshift alterations, leading to increased mutation-associated neoantigen (MANA) generation. The dramatic response seen with immune checkpoint inhibitors (ICIs), which are orchestrated by MANA-primed effector T cells, resulted in the rapid development of these novel therapeutics within the landscape of MSI-H gastrointestinal cancers. Recently, several clinical trials have utilized ICIs as potential neoadjuvant therapies for MSI-H gastrointestinal cancers and demonstrated deep clinical and pathological responses, creating opportunities for organ preservation. However, there are potential challenges to the neoadjuvant use of ICIs for certain disease types due to the clinical risk of overtreatment for a disease that can be cured through a surgery-only approach. In this review article, we discuss neoadjuvant management approaches with ICI therapy for patients with MSI-H gastrointestinal cancers, including those with oligometastatic disease. We also elaborate on potential challenges and opportunities for the neoadjuvant utilization of ICIs and provide further insight into the changing treatment paradigm of MMR-D/MSI-H gastrointestinal cancers.

Keywords: gastrointestinal cancers; immune checkpoint inhibitors; immunotherapy; neoadjuvant therapy.

Figure 1

MSI-H Colorectal Cancer Tumor Microenvironment: Released chemokines (CXCL9, CXCL10, and CXCL11) recruit and activate mutation-associated neoantigen (MANA)-specific cytotoxic T cells, NK cells, and dendritic cells. CD8+ TILs cells and NK cells secrete TNF-α and granzymes/perforins, leading to the cytolytic effect of tumor cells. CD4+ TILs secrete IL-1, IL-6, and IFN-γ and dendritic cells secrete IFN-γ. The release of IL-1, IL-6, and TNF-α promotes the formation of M1 macrophages, leading to antitumor effect. Secreted IFN-γ stimulates NK cells and CD4+ TILs, leading to antitumor effect.