Current landscape of immunotherapy in esophageal cancer: a literature review

Introduction

Background

Esophageal cancer has witnessed a significant shift in its epidemiology within the United States. Adenocarcinoma of the esophagus is now the fastest-growing solid malignancy, surpassing esophageal squamous cell carcinoma (ESCC) in frequency. Incidence rates are around 13,000 cases per year, and esophageal carcinoma ranks as the seventh leading cause of cancer-related deaths (1). The stage of disease at diagnosis stands as the foremost prognostic determinant. However, the challenge lies in the fact that by the time symptoms manifest, the disease has often progressed to a systemic stage, rendering surgical resection unfeasible. Regardless, surgical resection remains the optimal strategy for improved survival.

Rationale

• Unmet clinical need:
  • High mortality rate: esophageal cancer, particularly ESCC, has a high mortality rate and poor prognosis. Although not the optimal therapy, chemoradiation remains an effective treatment for ESCC (2).
  • Limited effective treatments: many patients relapse or do not respond to conventional therapies, necessitating the exploration of novel treatment options.
• Promising potential of immunotherapy:
  • Checkpoint inhibitors: both pembrolizumab and nivolumab have demonstrated efficacy in multiple studies, including in patients with advanced esophageal cancer (3-7).
  • Combination therapies: combining immune checkpoint inhibitors (ICIs) with chemotherapy or other targeted therapies has the potential to enhance efficacy and overcome resistance seen with monotherapies.
• Encouraging clinical trial results:
  • Recent trials (e.g., KEYNOTE-590, CheckMate-648) have demonstrated significant survival benefits in using ICIs for esophageal cancer, indicating a paradigm shift in treatment approaches.
  • These trials provide a foundation for further research and optimization of immunotherapy protocols.
• Biomarker development:
  • The identification and validation of predictive biomarkers [e.g., programmed death-ligand 1 (PD-L1) expression] are crucial for personalizing immunotherapy and improving patient outcomes (8).
  • Ongoing research aims to identify additional biomarkers that can predict response to ICIs (9).

Information gaps

• Long-term efficacy and safety:
  • While short-term results are promising, there is limited data on the long-term efficacy and safety of ICIs in esophageal cancer patients.
  • Studies are needed to assess the durability of response and potential late-onset adverse effects.
• Biomarker validation:
  • Although PD-L1 is a commonly used biomarker, its predictive value is not fully understood, and not all patients with high PD-L1 expression respond to ICIs (10).
  • There is a need for more robust and reliable biomarkers to guide treatment decisions.
• Mechanisms of resistance:
  • The underlying mechanisms of primary and acquired resistance to ICIs in esophageal cancer are not well understood.
  • Research into the tumor microenvironment (TME), genetic mutations, and immune evasion strategies is crucial to overcome resistance and improve response rates.
• Optimal combination therapies:
  • While combination therapies have shown potential, the optimal combinations, sequencing, and dosing regimens are still being explored.
  • Comparative studies are needed to identify the most effective combinations and to understand the interactions between different therapies.
• Patient selection criteria:
  • More research is required to refine patient selection criteria to identify those who will benefit most from immunotherapy.
  • This includes understanding the role of tumor histology, genetic profiles, and immune signatures.
• Quality of life and cost-effectiveness:
  • Data on the impact of immunotherapy on patients’ quality of life is limited.
  • Economic analyses to assess the cost-effectiveness of ICIs compared to traditional therapies are also needed to inform healthcare policy and reimbursement decisions.

Objectives

The primary objective of this paper is to provide a comprehensive review of the current landscape of immunotherapy in the treatment of esophageal cancer, with a specific focus on the following aspects:

• Overview of immunotherapy approaches:
  • To describe the different types of immunotherapies being investigated and used in clinical practice, including ICIs, adoptive cell therapies, and cancer vaccines.
• Evaluation of clinical efficacy and safety:
  • To summarize and critically analyze the findings from key clinical trials involving immunotherapeutic agents in esophageal cancer, highlighting their efficacy, safety profiles, and survival outcomes.
• Biomarkers and patient selection:
  • To discuss the role of biomarkers in predicting response to immunotherapy, current challenges in biomarker validation, and strategies for improving patient selection criteria to optimize treatment outcomes.
• Mechanisms of resistance:
  • To explore the known and hypothesized mechanisms underlying primary and acquired resistance to immunotherapy in esophageal cancer, and to suggest potential strategies to overcome these barriers.
• Combination therapies:
  • To review the rationale, clinical evidence, and ongoing research on combining immunotherapy with other treatment modalities (e.g., chemotherapy, targeted therapy, radiotherapy) to enhance therapeutic efficacy.
• Future directions and research priorities:
  • To identify critical gaps in the current knowledge and propose future research directions that could advance the field of immunotherapy for esophageal cancer, including the development of novel therapeutic agents and personalized treatment approaches.
• Quality of life and economic considerations:
  • To assess the impact of immunotherapy on patients’ quality of life and to evaluate the cost-effectiveness of these treatments in the context of healthcare systems.

By achieving these objectives, the paper aims to provide valuable insights for clinicians, researchers, and policymakers, facilitating the development of more effective and personalized immunotherapeutic strategies for esophageal cancer patients. We present this article in accordance with the Narrative Review reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1145/rc).

Methods

A literature search was conducted to identify all the studies published within the last 20 years on the topic of immunotherapy for esophageal cancer and the developments in immunotherapy in the past two decades. Candidate studies were sought through a computerized in PubMed, MEDLINE, and Google Scholar database. Keywords entered in this search were “esophageal cancer”, “immunotherapy in esophageal cancer”, and “immunotherapy”. Articles were limited to those published in English. Manual evaluation of the reference lists of the retrieved articles and reviews on the subject area was additionally performed. Please see Table 1 for the breakdown of the search strategy.

The current landscape of immunotherapy

Immunotherapy concept

Extensive research has highlighted the immune system’s role in both cancer cell elimination and tumor progression promotion. Tumors utilize various strategies, such as suppressor immune cell recruitment and production of immunosuppressive factors, to evade immune destruction.

Immune checkpoint modulation

Immune checkpoint molecules like programmed cell death protein 1 (PD-1) and PD-L1 play key roles in regulating immune responses. These checkpoints avoid excessive T-cell activation to maintain balance. Tumor cells expressing PD-L1 inhibit cytotoxic T lymphocytes (CTLs) by engaging the PD-1 receptor, inducing inhibitory signals that curb immune activity. This mechanism, while vital for immune regulation, is hijacked by tumors to evade immune destruction. In the normal immune pathway, T cells first recognize abnormal cancer cells and generate an immune response with CTLs that traffic to and bind and kill cancer cells. Tumor cells that express PD-L1 can neutralize these CTLs through engagement of the PD-1 receptor. PD-1 is a receptor that is expressed on the surface of activated T-cells and the binding of PD-L1 to this receptor reduces cytokine production and proliferation through an inhibitory signal (8). In a normal functioning immune system, PD-1/PD-L1 plays an important role in regulation and a deficiency has been shown to lead to autoimmune diseases in animal models (11). The body plays a balancing act that can be tipped by cancer to the patient’s detriment.

Mechanisms of resistance

The basis of the function of anti-PD-1/PD-L1 therapy is through the strengthening of preexisting CD8⁺ T-cells. Patients can have both primary and acquired resistance to PD-1/PD-L1 immunotherapy. A more complete understanding of tumor susceptibility, mechanisms of resistance, and methods to overcome resistance is necessary. A TME can be changed in varying ways to impede the antitumor efficacy of the T cells through insufficient antigen immunogenicity, dysfunction of antigen presentation, resistance to interferon (IFN)-γ signaling, and irreversible T cell exhaustion (12).

PD-1/PD-L1 interaction leads to effector T-cell inactivation and subsequent immune system evasion. Thus, by blocking this interaction cancer cells should lose the ability to escape the T-cell response. However, JAK1/2 inactivation mutations, methylation of PD-L1 promoter, and c-Myc expression have all been cited in contributing to acquired immune modulator resistance due to down-regulation of PD-L1. Acquired resistance can also be secondary to the down-regulation of B2M, leading to decreased major histocompatibility class I (MHC-I) expression, and subsequent escape from CD8⁺ T cells. Primary resistance can be due to initial low PD-L1 expression, low tumor mutation burden (TMB), deficient mismatch repair (MMR), and low microsatellite instability (MSI). Additionally, tumor-associated macrophages (TAMs) can favor the anti-tumor M2 subtype in the presence of indoleamine 2,3-dioxygenase, and prevent reactivation of T-cells (13).

The antitumor efficacy of PD-1/PD-L1 depends on antigen-specific T-cell reactivity in the TME. Essentially, it has been found that the tumors with the highest mutational burdens were more sensitive to anti-PD-1/PD-L1 therapy as they are more capable of generating neoantigens that induce antigen-specific T-cell reactivity (13). This translates to tumors that are deficient in MMR genes being particularly susceptible given their high number of mutagens that would generate neoantigens (14). The reverse holds true in tumors that lack the mutational burden being less likely to be responsive to therapy (15).

The basis for antigen presentation relies on MHC-I molecules and can be a target of resistance by the TME to T-cell activation through the inactivation of the MHC-I complex.

T-cell exhaustion is normally driven by high levels of antigens that persist following the failure of the host immune response to effectively clear the insult. These exhausted T cells have been shown to have unique transcriptional and epigenetic signatures that lead to an overexpression of several inhibitory receptors, altered metabolic fitness, and a dysregulated cytokine signaling pathway (16). Of these overly expressed inhibitory receptors, PD-1 is included and if this is present, results in resistance to anti-PD-1 treatment (17). Thus, to better predict the effect of anti-PD-1 therapy, one can look at numerous factors. PD-L1 expression, TMB, MSI, and serum microRNAs are possible considerations to predict ICI treatment effectiveness. TCR diversity was a predictor of response in dual ICI and radiotherapy treatments (13).

Overcoming resistance

Given the multiple mechanisms that tumors have at their disposal for anti-PD-1 resistance, one must consider different modalities to combine with anti-PD-1/PD-L1 therapy in order to achieve better clinical outcomes. Some current modalities focus on reversing T-cell exhaustion, increasing T-cell infiltration, and improving the immunosuppressive microenvironment (12). A combination of PD-1/PD-L1 inhibitors with chemotherapy, radiotherapy, chemoradiotherapy, other types of ICIs, chemokine/cytokine blockade, and transforming growth factor (TGF)-β blockade have shown potential for better tumor response (13).

Chimeric antigen receptor T-cell (CAR-T) therapy

CAR-T cell therapy is an immunotherapy that relies on genetically engineered CAR T-cells, designed to recognize tumor-associated antigens (TAAs) and initiate an attack on tumor cells. Specific esophageal cancer TAAs include human epidermal growth factor receptor 2 (HER2), mucin 1 (MUC1), CD276, and erythropoietin-producing hepatocellular receptor A2 (EphA2). Cancer vaccines to specific esophageal cancer TAAs such as New York ESCC 1 (NY-ESO-1), melanoma-associated antigen-A (MAGE-A), and cholesteryl pullulan-NY-ESo-1 (VHP-NY-ESO-1), kinase of the outer chloroplast membrane 1 (KOC1), and TTK protein kinase are being investigated. Cytokines and growth factors that aid tumor growth and suppress the body’s anti-tumor response such as TGF-β, a molecule that has distinct effects on the TME, regulatory T cells (Tregs), effector T cells, natural killer (NK) cells, dendritic cells, naive T cells, interleukin (IL)-2, cancer-associated fibroblasts (CAFs). Proinflammatory IL-6 impacts epithelial-mesenchymal transition (EMT), clonogenicity, chemoresistance, maturation of dendritic cells, and migration of ESCC cells. IL-10 is implicated in Treg upregulation, contributing to TIL exhaustion. Tregs suppress anti-tumor immunity and infiltrate tumor stroma. Tregs activity is controlled, among other immunologic agents, by CCL22, NY-ESO, and CCL4. T helper 17 cells (Th17) can promote tumor invasion via IL-17. A TME with predominant M2 TAMs promotes tumorigenesis and is associated with higher levels of TGF-β and PD-L1. Myeloid-derived suppressor cells inhibit T-cell-regulated tumor clearance, activate Tregs, and encourage M2 macrophages (10).

Combination strategies

Given tumors’ diverse resistance mechanisms, combining anti-PD-1/PD-L1 therapy with other modalities is a potential solution. Combinations with chemotherapy, radiotherapy, other ICIs, and growth factor blockade have shown potential.

Current treatment practices in locally advanced esophageal cancer

Despite more frequent detection of early esophageal cancer on surveillance endoscopies, most patients do not present until they become symptomatic. This generally signifies transmural tumor involvement (T3) with an 80% chance of lymph node involvement, meaning the staging on presentation is T3N1–3 (18). Immunotherapy, particularly ICIs like nivolumab and pembrolizumab, has shown promise in treating both early-stage and advanced esophageal cancer. Recent trials, including KEYNOTE-590 and CheckMate-648, have demonstrated significant improvements in overall survival for patients with advanced ESCC ultimately leading to FDA approval of pembrolizumab and nivolumab as first-line treatment along with chemotherapy in the setting of advanced or unresectable ESCC (Table 2) (3,4). Nivolumab, used as a first-line therapy in combination with chemotherapy, has led to improved survival rates and prolonged progression-free intervals. This success emphasizes the potential for immunotherapy to reshape the standard of care, particularly in tumors with high PD-L1 expression or high MSI (10).

The ESOPEC trial compared neoadjuvant chemoradiotherapy followed by surgery with perioperative FLOT chemotherapy in patients with locally advanced esophageal adenocarcinoma. Its results indicated that perioperative FLOT chemotherapy might be superior to chemoradiotherapy in improving long-term outcomes, leading to a potential paradigm shift in managing esophageal adenocarcinoma. This change emphasizes the need to refine treatment protocols to achieve better survival rates and reduce recurrence risks, suggesting that perioperative chemotherapy may become a new standard of care for certain esophageal cancer subtypes (19).

The CheckMate-577 trial was the next step in advancing care for these patients. This was a pivotal phase 3 trial that assessed the efficacy of nivolumab as adjuvant therapy for patients with esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy and had not achieved a pathologic complete response (pCR). The trial aimed to determine whether nivolumab could improve disease-free survival (DFS) compared to a placebo (5).

Key findings

• Improved DFS: the trial demonstrated that patients receiving nivolumab had a statistically significant improvement in DFS compared to those receiving a placebo. This was particularly notable in patients with tumors expressing PD-L1, suggesting that nivolumab could benefit those with specific tumor characteristics.
• Safety profile: nivolumab was generally well-tolerated, with a safety profile consistent with previous studies of the drug in other malignancies. This is significant as it suggests that nivolumab can be administered without excessive toxicity, making it a viable option for patients’ post-surgery (5).

Table 2 summarizes recent landmark trials and their conclusions. However, challenges remain, including understanding mechanisms of resistance. Primary resistance has been linked to factors like low PD-L1 expression or low tumor mutational burden, while acquired resistance may result from immune escape mechanisms such as JAK1/2 mutations or downregulation of MHC-I (12). To overcome these, combination therapies that integrate immunotherapy with chemotherapy, radiotherapy, or other immune-modulating treatments are being actively explored in ongoing clinical trials.

PD-L1 has emerged as a critical biomarker for determining ICI response, though further research is needed to refine patient selection criteria. MSI-high tumors are particularly sensitive to ICIs, and ongoing investigations into biomarkers may help personalize therapy, improving outcomes while minimizing unnecessary treatment (14).

The paradigm shift toward immunotherapy in esophageal cancer is promising, but optimizing the balance between efficacy, safety, and long-term outcomes remains an area of active research. Future studies will need to focus on overcoming resistance, expanding treatment to broader patient populations, and improving cost-effectiveness and quality of life.

Future directions

PD-L1’s role as a predictive biomarker for ICI response varies across cancer types. While cut-offs like combined positive score (CPS) =10 or tumor proportion score (TPS) =1% are useful, exceptions exist, with some PD-L1-negative tumors still responding well. Ongoing studies aim to refine treatment regimens and explore combination strategies to enhance ICI efficacy. Additionally, first-line ICI treatments are gaining momentum, with multiple trials showing promise. Recent research has also identified angiogenesis-associated proteins (IL-8, TIE2, and HGF) as potential predictive biomarkers for ICI response in esophageal cancer. The study by Gao et al. established an angiogenesis-related risk score that may improve prognostic accuracy and support the combined use of antiangiogenic therapies with ICIs to enhance survival outcomes (20). Similarly, inflammation-based prognostic scores such as the prognostic nutritional index (PNI), C-reactive protein-to-albumin ratio (CAR), and neutrophil-to-lymphocyte ratio (NLR) have been shown to correlate with treatment outcomes in patients receiving pembrolizumab and chemotherapy for advanced esophageal cancer. Sugase et al. demonstrated that pretreatment PNI could serve as an independent predictor of progression-free survival and overall survival, further supporting the need for validated biomarkers in optimizing therapeutic strategies (21). Future studies are needed to validate these findings and further refine biomarker-driven treatment approaches.

Conclusions

Esophageal cancer treatment is undergoing a paradigm shift with the advent of immunotherapy, particularly PD-1/PD-L1 inhibitors. These therapies hold promise for both second-line and first-line settings, with evolving biomarkers guiding treatment decisions. Combination strategies and personalized approaches are actively investigated to overcome resistance mechanisms and enhance treatment outcomes in this challenging cancer type.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1145/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1145/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1145/coif). The authors have 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.

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