Exploring immunotherapy in colorectal cancer

Abstract

Chemotherapy combined with or without targeted therapy is the fundamental treatment for metastatic colorectal cancer (mCRC). Due to the adverse effects of chemotherapeutic drugs and the biological characteristics of the tumor cells, it is difficult to make breakthroughs in traditional strategies. The immune checkpoint blockades (ICB) therapy has made significant progress in the treatment of advanced malignant tumors, and patients who benefit from this therapy may obtain a long-lasting response. Unfortunately, immunotherapy is only effective in a limited number of patients with microsatellite instability-high (MSI-H), and segment initial responders can subsequently develop acquired resistance. From September 4, 2014, the first anti-PD-1/PD-L1 drug Pembrolizumab was approved by the FDA for the second-line treatment of advanced malignant melanoma. Subsequently, it was approved for mCRC second-line treatment in 2017. Immunotherapy has rapidly developed in the past 7 years. The in-depth research of the ICB treatment indicated that the mechanism of colorectal cancer immune-resistance has become gradually clear, and new predictive biomarkers are constantly emerging. Clinical trials examining the effect of immune checkpoints are actively carried out, in order to produce long-lasting effects for mCRC patients. This review summarizes the treatment strategies for mCRC patients, discusses the mechanism and application of ICB in mCRC treatment, outlines the potential markers of the ICB efficacy, lists the key results of the clinical trials, and collects the recent basic research results, in order to provide a theoretical basis and practical direction for immunotherapy strategies.

Keywords: Biomarkers; Immune checkpoint blockade; Immune desert; Immunotherapy; Metastatic colorectal cancer; Microsatellite instability; Precision medicine.

Fig. 1

Proportion of dMMR/MSI-H in different tumor stages

Fig. 2

Mechanism of therapeutic resistance in ICB treatment. The reasons can be summarized as follows: insufficient tumor antigen presentation, tumor antigen presentation damage, T cell exclusion, and immunosuppressive signaling in the TME. The corresponding clinical trials are also marked in the figure

Fig. 3

Consensus molecular classification (CMS) and the coordinate immune response cluster (CIRC) typing of CRC

Fig. 4

Controversial roles of IFN-γ in the TME of CRC. Antitumor: IFN-γ signaling from immune cells and a high IFNG.GS/ISG.RS ratio were associated with increased CD8+ T cells and NK cell activation, and high response to ICB immunotherapy. IFN-γ can prompt CD8+ T cells and NK cells infiltration into TME, promote the MHC-I expression, boost Th1 cells polarization, directly induce tumor cells apoptosis or non-apoptotic death, establish tumor cells dormancy and inhibit tumor cells proliferation by IFN-γ/STAT1 pathway or non-STAT1 signaling; immune evasion: IFN-γ signaling released by tumor cells and a low IFNG.GS/ISG.RS ratio were associated with resistance to ICB treatment. IFN-γ can induce tumor antigen loss, recruit MDSC and TAMs into the TME, induce tumor immunoediting, and facilitate the expression of PD-L1, IDO, and arginase in TME

Fig. 5

Timeline of ICB therapy in MSI-H/dMMR CRC