Immunotherapy resistance in colorectal cancer with liver metastases: challenges & therapeutic advances

Introduction

Colorectal cancer (CRC) is the third most common cancer worldwide, with over 1.9 million new cases and nearly a million deaths reported in 2020 (1,2). By 2040, these figures are projected to rise to 3.2 million cases and 1.6 million deaths annually (2). In the United States alone, the incidence and mortality rates are expected to reach 147,000 cases and 34,000 deaths per year, respectively, by 2040 (3). This poor outlook is partly due to the late diagnosis of the disease, often when metastases have already developed, coupled with its aggressive nature. Despite significant advances in CRC screening over the past two decades, about 25–30% of patients are still diagnosed at an advanced stage, and up to 50% of those diagnosed early will eventually develop metastatic disease (4,5). The liver is the most common site for CRC metastases, present in up to 25% of patients at diagnosis (synchronous metastases) (6-8).

The standard care for CRC with liver metastases (CRCLM) involves surgical resection (for those with limited disease) and locoregional and liver-directed therapies, including radiotherapy and systemic therapy (9-11). However, challenges such as treatment resistance (genetic or sporadic), unresectable tumors, and the presence of other extrahepatic metastatic sites significantly hinder these traditional treatments, resulting in a 5-year survival rate as low as 30% (12-15). Consequently, there is a pressing need to develop more effective therapies for CRCLM. Immunotherapy has emerged as a promising treatment option in the past decade, enhancing the patient’s immune system by boosting humoral and cellular immunity and targeting immunosuppressive tumor-associated macrophages (TAMs) and other immune regulatory cells in the tumor microenvironment (TME) (16). It has proven effective in treating several solid cancers, such as melanomas and lung cancers, and has improved survival rates (17-19). It is also an important treatment option for metastatic CRC.

The effectiveness of immunotherapy in CRC depends on the status of the DNA mismatch repair (MMR) mechanism. This system corrects mismatched bases missed by DNA polymerase, thereby maintaining genetic integrity (20). A deficiency in this MMR (dMMR) system leads to a microsatellite instability-high (MSI-H) status, characterized by repetitive short sequences of nucleotides prone to replication errors (21). CRC can be classified based on the MMR status: tumors with dMMR/MSI-H status often have a high mutation burden. In contrast, those with preserved MMR/microsatellite stable (pMMR/MSS) status are more likely to present with a low burden (22). A high tumor mutation burden (TMB) creates an immunogenic microenvironment by producing several neoantigens. It has been shown to predict improved overall survival with immunotherapy in multiple solid cancers, including CRC (23,24). Therefore, dMMR/MSI-H CRCs generally respond well to immunotherapy, unlike pMMR/MSS cancers, which comprise 95% of metastatic CRCs (25). However, regardless of the MSI status, the presence of liver metastases (LMs) compared to non-LMs has been linked with reduced immunotherapy efficacy in CRC (26).

We briefly review the evidence for immunotherapy challenges in CRCLM, resistance mechanisms, potential therapeutic options, and areas for further research.

LMs: a barrier to effective immunotherapy?

Recent studies have suggested the adverse effect of LMs on the efficacy of immunotherapy in patients with CRCLM (Table 1). An open-label phase 1b trial (27) evaluated the effect of regorafenib [a tyrosine kinase inhibitor (TKI)] and nivolumab (a PD-1 inhibitor) in patients with metastatic pMMR/MSS CRC who had progression of the disease despite receiving at least two lines of standard chemotherapy. The objective response rate (ORR) for those with LM (8.3%) was lower than for those with lung metastases without liver involvement (63.6%). These findings were further confirmed by a single-arm, phase II trial of nivolumab and regorafenib in patients with advanced CRC. Compared to those without LM, patients with LM had a lower overall and partial response rate (21.7% vs. 0%) (28).

Chen et al. (29) conducted a post-hoc analysis of a randomized phase II clinical trial of the effect of LM on the efficacy of immune checkpoint inhibitors (ICIs) in patients with treatment-refractory advanced CRC, irrespective of the MSI status. On univariate analysis, median progression-free survival (PFS) improved significantly in the durvalumab plus tremelimumab group among patients without LM {1.82 months [90% confidence interval (CI): 1.71–1.84] vs. 2.04 months (90% CI: 1.87–3.71)}. The disease control rate (DCR) was also significantly higher in the durvalumab plus tremelimumab group among patients without LM (10% vs. 49%). On multivariable analysis, after controlling for TMB and sex, patients with LM had significantly worse overall survival (OS) compared to patients without LM [hazard ratio (HR), 1.97; 90% CI: 1.42–2.72].

A retrospective study (30) comprising 95 patients (41 with LM and 54 without LM) evaluated the association of LMs with response to anti-programmed death-1/ligand-1 (PD-1/PD-L1) inhibitors in patients with pMMR/MSS metastatic CRC. In this study, patients without LM had an ORR of 19.5% (8 out of 41 patients), but there was no response in 54 patients with LMs. Furthermore, this study also found that patients without LM had a DCR of 58.5% (24 of 41) but 1.9% (1 of 54) in those with LM. PFS was also superior in those without LM compared to those with LM {4.0 [interquartile range (IQR), 2.0–7.5] vs. 1.5 (IQR, 1.0–2.0) months; P<0.001}. Lastly, this study found that after adjusting for Eastern Cooperative Oncology Group status, primary tumor location, RAS and BRAF status, TMB, and metastatic sites, LM was the variable with the most significant association with faster progression after treatment with anti-PD-1/PD-L1 (HR, 7.00; 95% CI: 3.18–15.42; P<0.001).

A recent open-label phase III LEAP-017 study (31) with pembrolizumab and lenvatinib observed improved OS, PFS, and ORR in patients without LM compared with investigators’ choice of regorafenib or trifluridine and tipiracil. In the phase I trial, botensilimab, an enhanced cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody, was combined with balstilimab (anti-PD-1 antibody) in pMMR/MSS metastatic CRC. ORR in those with LM was 0% compared to 17% vs. 22% in those without LM (32).

This observed poor response to immunotherapy in patients with LM is not unique to metastatic pMMR/MSS CRC. Saberzadeh-Ardestani et al. (33) reported reduced antitumor response among dMMR/MSI-H CRCLM compared to those without LM. Hence, the limited immunotherapy response seen in the setting of LMs appears to be independent of MSI status.

Liver TME and mechanisms of resistance to immunotherapy in CRLM

The liver TME is a complex ecosystem composed of cancer cells and non-cancer cells such as immune cells (e.g., T cells, macrophages, dendritic cells), stromal cells (e.g., fibroblasts, endothelial cells), extracellular matrix components and signaling molecules (e.g., cytokines, chemokines, growth factors) (34-36). The interaction of cellular and non-cellular elements of the TME of the liver with cancer cells plays a vital role in tumor-related inflammation, progression, angiogenesis, and metastases (37-39). Several factors in the liver TME have been linked to immune resistance of CRCLM to immunotherapy (Figure 1). The liver TME in CRCLM presents a uniquely more immune-suppressive and immunotolerant milieu (40,41). Zhou et al. (41) compared the expression of infiltrating immune cells (CD3⁺ cell, CD8⁺ cell, CD11b⁺ cell, CD11c⁺ cell, and CD33⁺ cell) in resected tumors from the primary and hepatic metastatic sites in 54 patients with CRCLM. They found higher expression of the CD33 marker in the tumor center in hepatic metastases than in primary tumors. On the contrary, CD8⁺ and CD3⁺ cells were more significantly expressed in the primary tumor than in hepatic metastases. CD8⁺ and CD3⁺ cells are generally regarded as markers of T-cell infiltration (42,43), which may predict a good response to immunotherapy. On the contrary, CD33, expressed on myeloid-derived suppressor cells (MDSCs), which also elaborates vascular endothelial growth factor (VEGF), which binds vascular endothelial growth factor receptor (VEGFR), inhibits T-cell proliferation (44), which may contribute to the poor response to immunotherapy in CRCLM.

Figure 1 Liver tumor micro-environment and putative mechanisms of resistance to immunotherapy in colorectal cancer with liver metastases. Created in BioRender. Ilerhunmwuwa NP. 2024:p35e776 (https://BioRender.com). TME, tumor microenvironment.

Yu et al. (40) demonstrated in multiple mouse models that LMs may eliminate activated CD8⁺ T cells from the systemic circulation and that within the liver, activated antigen-specific Fas⁺CD8⁺ T cells undergo apoptosis following their interaction with FasL⁺CD11b⁺F4/80⁺ monocyte-derived macrophages. This process creates an immunologically “inert” TME, which consequently facilitates the progression of cancerous cells. They also found reduced CD8⁺ T cell infiltration in mice with hepatic metastasis, failing to respond to anti-PD-L1 therapy.

Li et al. (45) identified a factor, fibrinogen-like protein 1 (FGL1), elaborated by both cancer and native liver cells and stabilized by OTU deubiquitinase 1 (OTUD1) expression via TAMs. This protein was significantly elevated in hepatic metastases, with levels negatively correlated with response to PD-1 blockade and overall survival.

Hou et al. (46) reported excessive production of artemin from CD45⁻Ter119⁺CD71⁺ erythroid progenitor cells in the presence of LM. Artemin is a neurotrophic peptide that promotes tumor progression and induces resistance to immunotherapy by stimulating the REarranged during Transfection (RET) signaling (46).

Future directions in immunotherapy landscape for CRCLM

There is ongoing research on bypassing or suppressing these factors in the liver TME to enhance responsiveness to immunotherapy in CRCLM. In CRCLM, lymphocyte activation gene 3 (LAG-3) receptors were strongly expressed on cytotoxic CD8⁺ T cells, CD4⁺ T-helper, and/or regulatory T (Treg)-cells compared with tumor-free liver. These receptors inhibit the activation of these cells, creating an immunosuppressive TME. Antibody blockade of the LAG3 receptors has been linked to increased proliferation and production of cytokines [interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) secretion], CD8⁺, and CD4⁺ tumor-infiltrating lymphocyte (TIL) compared with the controls without the inhibitory antibodies (47). Therefore, LAG3 receptors on T lymphocytes in CRCLM may be a potential immunotherapeutic target or partner in combination immunotherapy regimens. In a recent open-label, phase II study (48) which evaluated the efficacy of nivolumab (anti-PD-1) and relatlimab (anti-LAG) in previously treated patients with MSI-H/dMMR metastatic CRC, ORR in patients with LMs was 39%, which is higher than previously reported ORR (33).

Another potential target in the liver TME that has shown promise is the VEGF/VEGFR signaling pathway. Previous studies that evaluated TKI with anti-VEGFR effects showed less-than-desirable response rates in LMs. However, the CAMILLA trial (49) suggested improved immunotherapy efficacy with a novel TKI—cabozantinib—in pMMR/MSS CRCLM. The response rate in this trial in LMs was 17.9%, which is higher than the ORR reported in previous studies (28,31-32). This study informed the phase III STELLAR-303 trial to validate the findings on a larger scale (50).

In their orthotopic mouse model, Fiegle et al. (51) reported that dual immune checkpoint blockade of PD-L1 and CTLA-4 reduced colon cancer growth and blocked LMs. The dual inhibition significantly increased intra-tumoral cytotoxic CD8⁺ and CD4⁺ T cells resulting in the elaboration of pro-inflammatory Th1/M1-related cytokines IFN-γ, interleukin (IL)-1α, IL-2, and IL-12 (these cytokines have antitumor activity), and reduced expression of FOXP3⁺/CD4⁺ Treg cells (these cells have immunosuppressive activity and create immunotolerance in the TME). It was also associated with increased intra-tumoral iNOS⁺ macrophages, reduced PD-L1⁺ and Tie2⁺ macrophages, and the low expression of M2/Th2-related IL-4, TARC, and COX-2. However, in a recent phase I trial, this dual combination of CTLA-4 and anti-PD-1 inhibition did not translate into clinical benefits in patients with CRCLM (32).

There is an increasing interest in the role of gut microbiome and the progression of CRCLM. The intestinal gram-negative microbes produce lipopolysaccharide (LPS), linked to an increased influx of cancer cells into the liver (52). LPS stimulates Toll-like receptor 4 (TLR4) signaling and increases β1 integrin-mediated cell adhesion, enhancing CRCLM (53). Furthermore, LPS has also been associated with the migration of CRC cells by activating the SDF-1α/CXCR4 axis and EMT (51). The role of LPS in promoting an immune-tolerant TME was further validated by Song et al. (54), who utilized an orthotopic CRC model with a murine CRC cell line with high potential for LMs to show that engineered LPS-targeting fusion protein inhibited LPS inside the tumor with the consequent significant increase in responsiveness to anti-PD-L1 antibodies against the CRC tumor. The authors also showed that antibiotic treatment of the gut with polymyxin and inhibition of the TLR4, which is the receptor for LPS, was associated with increased infiltration of the tumor by cytotoxic T cells and concomitant decrease in myeloid-derived suppressor cells. However, these findings from pre-clinical studies are yet to be validated in human trials.

In mouse models, combining radiotherapy and anti-PD-1 therapy abolished the resistance to immunotherapy caused by LM by enhancing the proliferation of IFN-γ production and increasing cytotoxic T-cell infiltration into the tumor. This resulted in regression of LM and prolonged survival (40).

Several preclinical studies have demonstrated the synergistic effect of combining PD-1 blockade and COX inhibitors for tumor regression (55-57). In a recent phase II trial (58), which evaluated the efficacy and safety of this combination, 3 of the 30 patients with metastatic CRC had hepatic metastases, of which 2 had a partial objective response.

A potential therapeutic target in the liver TME is the TAMs, particularly the SPP1⁺ subset, which are predominant in LMs, anti-inflammatory, and pro-angiogenesis and are linked to the poor overall survival of CRC patients (59).

Due to the complexity of the TME in CRCLM, machine learning-based bioinformatics may provide further understanding of the several molecular mechanisms that may represent potential areas of therapeutic options and precision medicine (60). There is ongoing research on the therapeutic role of novel approaches such as CAR-T, bispecific antibodies, and vaccines in CRCLM to improve therapeutic response to immunotherapy in this patient population (61).

Conclusions

LMs in CRC are associated with reduced responsiveness to immunotherapy. Several factors in the liver TME could provide potential targets for immunotherapeutic strategies. Further research is needed to explore novel immunotherapeutic agents that could overcome or bypass the immune resistance in the liver TME in CRCLM.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-93/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-93/coif). I.H.S. received grants from Bayer, consulting fees from GSK, Guardant Health, Seagen, and honoraria from Pfizer and Amgen. A.S. reports receiving consulting fees from and involving with advisory board of AstraZeneca, Bristol-Myers Squibb, Merck, Exelixis, Pfizer, Xilio therapeutics, Taiho, Amgen, Autem therapeutics, KAHR medical, and Daiichi Sankyo; institutional research funding from AstraZeneca, Bristol-Myers Squibb, Merck, Clovis, Exelixis, Actuate therapeutics, Incyte Corporation, Daiichi Sankyo, Five prime therapeutics, Amgen, Innovent biologics, Dragonfly therapeutics, Oxford Biotherapeutics, Arcus therapeutics, and KAHR medical. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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