CEACAM5 Overexpression Enables Tumor Progression and Immune Evasion: Immunotherapeutic Targeting Considerations

Abstract

Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a ubiquitously expressed tumor-associated glycoprotein with limited expression in normal adult tissue. It operates in complex modes to enable cancer advancement, from enhanced cell adhesion and migration to immune evasion. Its overexpression is common in a wide range of malignancies, including colorectal, gastric, pancreatic, and lung cancers. Recent studies have enlightened the ways in which CEACAM5 supports immune escape mechanisms by interacting with suppressive immune receptors, thus weakening anti-tumor immunity. Such characteristics render CEACAM5 a promising target for immunotherapeutic strategies, including antibody-drug conjugates (ADCs), bispecific T-cell engagers, and CAR-T cell therapies. The current review addresses the biological function of CEACAM5, its implications in tumor growth and immune suppression, and the existing pipeline of therapeutic strategies under research. Challenges including tumor heterogeneity, on-target off-tumor toxicity, and resistance are also addressed, along with opportunities for more personalized, potent interventions. 

Introduction

Cancer continues to be one of the foremost causes of morbidity and mortality globally, with numerous solid tumors that are resistant to traditional therapies. The past two decades have seen increased emphasis on finding molecular targets capable of playing both diagnostic and therapeutic functions. Among them, CEACAM5 has emerged as a front-runner based on the fact that it is selectively expressed in cancerous tissues and plays a functional role in tumor development and modulation of immunity.

CEACAM5, previously called carcinoembryonic antigen (CEA), is most commonly associated with colorectal carcinoma but also found highly in pancreatic, gastric, breast, and non-small cell lung carcinoma. CEA has been used clinically as a serum marker for decades to monitor recurrence of disease or response to therapy, especially in colorectal carcinoma. However, recent findings indicate that CEACAM5 is not merely a bystander in cancer biology. It has an active role in tumor progression, metastasis, and immune escape, making it a target for therapeutic intervention[1].

Here, the authors provide an overview of the biological functions of CEACAM5 with an emphasis on its function in tumor development and immune escape. The article also discusses the current status of immunotherapeutic approaches targeting CEACAM5, encompassing clinical and preclinical advancements.

Biological Function of CEACAM5

CEACAM5 belongs to the carcinoembryonic antigen (CEA) family, a family in the immunoglobulin superfamily. CEACAM5 contains a single N-terminal IgV-like domain and several IgC-like domains, both with roles in intracellular signaling and cell-cell adhesion. CEACAM5 is anchored to the cell membrane by a glycosylphosphatidylinositol (GPI) moiety, where it is in position to interact at the cell surface.

During fetal development, CEACAM5 is strongly expressed in epithelial tissues, particularly in the gut. After birth, it gets downregulated, remaining nearly entirely undetectable in adult tissues except trace levels in the colon, lungs, and cervix. The developmental pattern of this type, termed oncofetal expression, renders CEACAM5 a superb target for cancer-specific therapy[2].

Functionally, CEACAM5 controls cell adhesion, polarity, and differentiation. It could promote homophilic (CEACAM5–CEACAM5) and heterophilic (CEACAM5–other CEACAMs) interactions, which would promote tumor cell aggregation and spread. CEACAM5 also controls intracellular signaling pathways such as PI3K/AKT and MAPK, which are implicated in growth and survival.

Its interaction with lipid rafts also supports its role as a signaling node, mediating responses to extracellular signals and involvement in tumorigenic phenotypes. Most particularly, these functions are targeted by cancer cells to achieve metastasis and resistance to cell death[3].

CEACAM5 in Tumor Growth and Immune Evasion

CEACAM5 overexpression in cancer is associated with more aggressive tumors and poor clinical prognosis. CEACAM5 is functionally involved in epithelial-mesenchymal transition (EMT) and enhances tumor cell motility and invasiveness. It also assists the formation of circulating tumor cell clusters that are proficient in the survival in the bloodstream and seeding metastases.

In addition to supporting tumor growth, CEACAM5 plays a key role in immune evasion. It interacts with immune-suppressive receptors such as CEACAM1 on T cells and natural killer (NK) cells. The interactions suppress the activation and cytotoxicity of immune cells so that tumor cells can escape immune detection[4].

Experiments have shown that CEACAM5-positive tumors are less competent to attract cytotoxic lymphocytes and have lower immune checkpoint expression, which corresponds to a "cold" tumor immune microenvironment. This is interesting because immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1) are typically less effective in these situations. Thus, overexpression of CEACAM5 may be utilized as a biomarker for resistance to immune checkpoint blockade.

CEACAM5 also impinges on the tumor stroma. It controls tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) activity, tipping the balance of the immune microenvironment toward immunosuppression. These functions are further complemented by CEACAM5-mediated inhibition of antigen presentation, dampening tumor-specific T cell priming[5].

These mechanisms together position CEACAM5 in the center not only in tumor cell biology but also in establishing an immunosuppressive niche that facilitates cancer development.

CEACAM5 as a Therapeutic Target

The restricted expression of CEACAM5 in adult normal tissues and high frequency in epithelial tumors make it an attractive target for immunotherapy. Multiple modalities to utilize the tumor specificity of CEACAM5 have been designed, which have different mechanisms of action.

Monoclonal Antibodies (mAbs)

Anti-CEACAM5 monoclonal antibodies such as labetuzumab have been reported to exhibit tumor-selective binding in preclinical studies. Initial unconjugated mAb trials were not very successful, but conjugation of the antibodies with toxins has proven more promising[6].

Antibody-Drug Conjugates (ADCs)

ADCs combine the specificity of the antibody with chemotherapy activity. Labetuzumab govitecan, which couples CEACAM5-targeting mAbs to SN-38 (an analog of the irinotecan), has shown preclinical efficacy against models of colon and pancreatic cancers. By targeted delivery of cytotoxins to cells expressing CEACAM5, ADCs lower systemic toxicity and enhance therapeutic ratio[7].

Bispecific T-cell Engagers (BiTEs)

BiTEs simultaneously bind CEACAM5 on tumor cells and CD3 on T cells and thereby engage cytotoxic T cells against tumor cells regardless of T cell receptor specificity. CEACAM5-CD3 BiTEs, in experiments, were found to induce strong T-cell activation and tumor lysis in animals and in vitro[8]. 

CAR-T Cells

Chimeric antigen receptor (CAR) T cells engineered to recognize CEACAM5 have also been produced. The engineered cells are antigen-specific and induce cytotoxicity and cytokine production upon co-culture with CEACAM5-expressing tumor cells. However, due to on-target, off-tumor toxicity against CEACAM5-low tissues, safety is a concern for clinical translation.

Vaccines and RNA-Based Therapies

Experimental CEACAM5 peptide-based vaccines are found to have immunogenicity and tumor control in preclinical models. In the same way, mRNA vaccine platforms that generate CEACAM5-targeting antibodies or TCRs are under development, which utilizes the recent advances in lipid nanoparticle delivery and immunostimulation.

Preclinical and Clinical Studies

Several studies confirm the feasibility of in vivo targeting of CEACAM5. In xenograft models, CEACAM5-targeting ADCs have broadly halted tumor growth and promoted survival without affecting normal tissues. These findings were particularly robust in models of colorectal, pancreatic, and gastric cancer.

Clinical trials have examined CEACAM5-targeting agents in different cancers. Manageable toxicity and disease stabilization in a subgroup of patients were seen in a phase I/II trial of labeuztumab govitecan in metastatic colorectal cancer. A trial using a CEACAM5-targeted BiTE had good pharmacokinetics and early signs of tumor reduction.

Early-stage trials evaluating CEACAM5 CAR-T cells in gastrointestinal malignancies are ongoing. These trials aim to establish the maximum tolerated dose and assess safety, with secondary endpoints focusing on immunogenicity and efficacy.

To enhance selectivity, researchers are developing CEACAM5-specific switchable CAR-T systems and dual-antigen targeting strategies. These approaches aim to minimize off-tumor effects while retaining anti-tumor efficacy[9].

Additionally, CEACAM5 has been explored as a companion biomarker. Its expression pattern can be exploited for selection of patients to be treated with targeted therapy and evaluation of response to therapy with circulating tumor DNA or serum.

Challenges and Future Perspectives

Despite encouraging advances, several issues stand in the way of full clinical utilization of CEACAM5-targeting therapies. One of these is the risk of on-target, off-tumor toxicity. Although CEACAM5 is not usually expressed in adult tissues, low-grade expression in gastrointestinal mucosa and other epithelia poses safety risks, particularly with potent immune effectors like CAR-T cells.

The other challenge is tumor heterogeneity. Not every CEACAM5-expressing tumor cell uniformly expresses it, creating a possible route of treatment escape and relapse. Dual-targeting CAR-T cells or combining CEACAM5-based treatments with more universal immune modulators could solve this problem.

Resistance mechanisms are also being developed. Tumors will downregulate expression of CEACAM5 or secrete soluble CEACAM5 to inactivate antibody-based therapies. Resistance will be overcome by a better understanding of the regulation of CEACAM5 and the necessity for adaptive treatment schemes.

Biomarker development is of essential importance. Identification of patients who will benefit from CEACAM5-targeting therapy will improve outcomes and avoid unnecessary treatment. Companion diagnostics like IHC, RNA profiling, and liquid biopsy are in the process of being optimized to meet this need.

Future research will likely focus on combination regimens, pairing CEACAM5-targeting agents with checkpoint inhibitors, radiation, or DNA-damaging agents to potentiate anti-tumor activities.

Fig. 1.CEACAM5-directed Antibody Drug Conjugate[10]

Conclusion

CEACAM5 plays a multidimensional role in the development of cancer, with roles in tumor growth, immune evasion, and metastasis. Its tumor-limited expression and functional value make it a compelling target for immunotherapeutic treatments. Advances in antibody engineering, CAR-T cell engineering, and ADC technology have placed CEACAM5 on the list for therapy. Despite the obstacles, clinical trials and translational research being conducted today keep pushing the boundaries of what can be done with CEACAM5 as a cancer therapy target.

References

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