Liver metastasis and resistance to immunotherapy in microsatellite stable colorectal cancer. A literature review

Abstract

Background: Microsatellite stable (MSS) metastatic colorectal cancer (CRC) remains predominantly managed with chemotherapy. The use of immunotherapy, whether alone or in combination with other systemic or local treatments, displays limited success, especially in the context of active liver metastases (LM). The mechanisms responsible for this resistance are not fully understood.

Methods: We conducted a comprehensive search across electronic databases such as Medline, PubMed, Google Scholar and ScienceDirect. This search targeted translational studies evaluating the liver tumour immune microenvironment and immune tolerance mechanisms in CRC with LM and prospective studies that assessed immunotherapy either as a standalone treatment or in combination with other systemic or local therapies for patients diagnosed with MSS CRC. Our primary objectives included elucidating the mechanisms of resistance originating from LM in a non-systematic literature review and presenting a summary of the outcomes observed in prospective trials utilising immune checkpoint inhibitors (ICIs), with a focus on the presence of LM.

Findings: There were 16 prospective trials evaluating immunotherapy for metastatic CRC comprising 1,713 patients. Response rates to immunotherapy inpatients with colorectal liver metastases (CRLM) varied from 0% to 23%. Overall, reduced or null responses to immunotherapy in the presence of liver metastasis in comparison to patients without liver involvement were observed.

Conclusion: Studies consistently show the resistance derived from classical ICI, both alone and in combination with other systemic treatments in patients with CRLM. The design of upcoming trials using immunotherapy should consider LM as a stratification factor or contemplate excluding patients with liver involvement.

Keywords: colorectal cancer; immunotherapy; liver metastasis; microsatellite stable.

Figure 1.. Impacts of CRLM on the hepatic immune microenvironment. Legend: Tumoural cells release exosomes that facilitate angiogenesis and enhance endothelial permeability. These exosomes also interact with KCs, prompting a shift towards a proinflammatory M2 phenotype and inducing apoptosis in NK cells and cytotoxic CD8+ T cells. The M2 macrophages, in turn, release TGF-beta, contributing to the differentiation of physiological HSCs into CAFs. Additionally, M2 macrophages downregulate ANGPTL1, resulting in heightened vascular permeability. Both N1 and N2 neutrophils stimulate VEGF production, thereby increasing angiogenesis. Furthermore, N2 and M2 cells secrete cytokines with immunosuppressive properties. These intricate interactions collectively contribute to a decline in CD8+ T cells and an elevation in Tregs, culminating in an augmented expression of TIM-3. Activation of TIM-3 induces dysfunction in NK cells and facilitates the transition of macrophages to the M2 phenotype, thereby perpetuating tumour progression and immunosuppression. N1, Neutrophil type 1; N2, Neutrophil type 2; KC, Kupffer cell; M1, Macrophage type 1; M2, Macrophage type 2; TGF-beta, Transforming growing factor beta; VEGF, Vascular endothelial growing factor; HSC, Hepatic stellate cell; CAF, Cancer-associated fibroblast; NK, Natural killer cell; TIM-3, T-cell immunoglobulin mucin 3.