Neuroendocrine tumours (NETs) are a diverse group of neoplasms originating from neuroendocrine cells, which possess characteristics of both nerve and endocrine cells.
The development and progression of NETs are influenced by various factors, including genetic mutations, hormonal imbalances, and notably, the immune system.
Understanding the immunological aspects of NETs is crucial for developing effective therapeutic strategies.
Neuroendocrine Cancer Australia (NECA), is dedicated to assisting individuals diagnosed with NETs and their loved ones. NECA offers a wealth of resources, educational programs, and advocacy efforts aimed at deepening the understanding of NETs, improving patient care, and encouraging research advancements. Patients can engage with NECA’s comprehensive support and information by calling the NET nurse line.
Overview of the immune system’s role in tumour surveillance
The immune system serves as the body’s primary defense mechanism against abnormal cells, including those that may develop into cancer.
Through a process known as immunosurveillance, immune cells such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells identify and eliminate transformed cells before they can proliferate uncontrollably.
This surveillance is mediated by the recognition of tumour-specific antigens presented on major histocompatibility complex (MHC) molecules. Effective antigen presentation is vital for the activation of CTLs, which then target and destroy aberrant cells.
Similarly, NK cells can detect and kill cells that exhibit stress markers or lack normal MHC class I expression, a common feature in malignant cells.
Immune evasion by neuroendocrine tumours
Despite the vigilant nature of the immune system, NETs have developed sophisticated mechanisms to evade immune detection and destruction. These evasion strategies enable tumours to establish and progress within the host.
Expression of immune checkpoint proteins
NETs may express immune checkpoint proteins such as programmed death-ligand 1 (PD-L1), which interact with programmed death-1 (PD-1) receptors on T cells to inhibit their activity. This interaction leads to T cell exhaustion and an inability to mount an effective anti-tumour response. The upregulation of PD-L1 has been observed in various NETs, facilitating immune escape and tumour progression.
Inflammatory conditions and tumour development
Chronic inflammation is a well-established factor that can promote tumour initiation and progression. Persistent inflammatory conditions create a pro-tumorigenic environment through the continuous release of cytokines and growth factors that induce DNA damage, support cellular proliferation, and inhibit apoptosis.
Cytokine imbalance and tissue damage
In the context of NETs, an imbalance of pro-inflammatory and anti-inflammatory cytokines can lead to tissue damage and create a milieu conducive to tumour development.
Autoimmune disorders and endocrine dysregulation
Autoimmune disorders that result in chronic inflammation and endocrine dysfunction may also contribute to NET development.
The continuous immune assault on endocrine tissues can lead to compensatory hyperplasia and an increased risk of neoplastic transformation.
Furthermore, the dysregulated immune environment in autoimmune conditions may facilitate the survival and proliferation of transformed neuroendocrine cells.
Key immune cells involved in NET progression
The tumour microenvironment of NETs comprises various immune cell types that can either promote or inhibit tumour progression.
Tumour-associated macrophages (TAMs)
TAMs are a prominent component of the NET microenvironment and are typically polarised towards an M2 phenotype, which supports tumour growth and suppresses immune responses. High densities of TAMs have been associated with increased tumour aggressiveness and poorer clinical outcomes in NET patients.
Regulatory T cells (Tregs)
Tregs play a crucial role in maintaining immune tolerance by suppressing the activity of effector T cells. In NETs, an abundance of Tregs within the tumour microenvironment can inhibit anti-tumour immune responses, facilitating tumour progression and metastasis. (Source: Karger)
Natural Killer (NK) cells
NK cells are essential components of the innate immune system, capable of recognising and killing tumour cells without prior sensitisation. However, in NET patients, NK cell activity is often impaired, reducing their effectiveness in controlling tumour growth. This impairment may result from the immunosuppressive tumour microenvironment or intrinsic defects in NK cell function.
Immunotherapy in the context of NETs
In recent years, immunotherapy has revolutionised cancer treatment by harnessing the body’s own immune system to identify and destroy cancer cells. While immunotherapy has shown success in melanoma, lung, and kidney cancers, its application in neuroendocrine tumours (NETs) is still an emerging area. The unique biology and typically low mutational burden of NETs present challenges, but several strategies are under investigation.
Immune checkpoint inhibitors
Immune checkpoint inhibitors (ICIs) are drugs that block proteins such as PD-1, PD-L1, and CTLA-4, which tumours use to suppress immune responses. By inhibiting these proteins, ICIs aim to restore T cell activity and enhance the immune system’s ability to attack tumour cells.
In well-differentiated, low-grade NETs, immune checkpoint inhibitors have generally shown limited success, likely due to the relatively low expression of PD-L1 and a low tumour mutational burden (TMB). However, in high-grade or poorly differentiated neuroendocrine carcinomas (NECs), which exhibit more genetic instability and higher PD-L1 expression, ICIs have demonstrated more promise.
Trials involving drugs like nivolumab and pembrolizumab have shown some responses in these aggressive NET subtypes. Nevertheless, these therapies are not yet standard practice and are typically reserved for patients with high-grade disease or those enrolled in clinical trials.
Cancer vaccines and T cell therapies
Cancer vaccines aim to stimulate the immune system to recognise and attack tumour-specific antigens. In NETs, vaccines targeting chromogranin A and other neuroendocrine markers are under investigation but remain in early phases of development.
Adoptive T cell therapies, including TIL (tumour-infiltrating lymphocyte) therapy and CAR T cell therapy, are also being explored. These involve modifying or expanding a patient’s own immune cells to better target cancer cells. While not yet clinically approved for NETs, preclinical studies suggest that these approaches may be beneficial in tumours with identifiable surface antigens and immune-accessible microenvironments.
Biomarkers of immune activity in NET patients
As researchers explore immunotherapy options for NETs, identifying reliable biomarkers to predict which patients will benefit is crucial. Biomarkers help assess the level of immune activation and can provide insights into treatment responses or resistance.
PD-L1 expression and Tumour Mutational Burden (TMB)
PD-L1 expression, measurable through immunohistochemistry, is a key biomarker in immunotherapy. High levels of PD-L1 on tumour cells are associated with a greater likelihood of response to PD-1/PD-L1 inhibitors. However, in most NETs, PD-L1 expression tends to be low, particularly in well-differentiated types.
Tumour mutational burden (TMB) reflects the number of genetic mutations within a tumour. A higher TMB generally leads to more neoantigens that can be recognised by the immune system, making the tumour more immunogenic. High-grade NETs, especially those resembling small cell carcinomas, tend to have higher TMB and may be more responsive to immunotherapy. Conversely, low-grade NETs typically have a low TMB and thus respond less well.
Circulating immune cell profiles
Beyond tissue-based biomarkers, blood tests are being developed to monitor systemic immune activity. Profiles of circulating immune cells (such as the ratios of CD8+ T cells to regulatory T cells (Tregs), or the presence of exhausted T cells) may provide a non-invasive way to track immune responses over time.
Emerging evidence suggests that NET patients with more robust systemic immune responses may have better prognoses and could be candidates for immunotherapy-based clinical trials. Further research is needed to validate these blood-based biomarkers and incorporate them into clinical decision-making.
Further information and support for people diagnosed with NETs is available by calling the NECAÂ NET nurse line.
Sources
Tumour Mutational Burden as a Predictor of Immunotherapy Response
https://www.cell.com/cancer-cell/fulltext/S1535-6108(18)30593-3PMC
Circulating Tumour Cells as Prognostic Markers in Neuroendocrine Tumours
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Immune Checkpoint Inhibitors in Neuroendocrine Tumours
https://pubmed.ncbi.nlm.nih.gov/30591017/
**CAR T-Cell Therapy Clinical Trial for Neuroendocrine Tumours**
Neuroendocrine Tumor Research Foundation (2023).
https://netrf.org/2023/11/20/research-milestone-in-netrf-funded-science-car-t-therapy-clinical-trial-announced-for-nets/NETRF+1NETRF+1
PD-L1 Expression in Large Cell Neuroendocrine Carcinoma of the Lung
https://pubmed.ncbi.nlm.nih.gov/29572007/Journal of Thoracic Oncology+5PubMed+5ScienceDirect+5
Prevalence of High Tumour Mutational Burden and Microsatellite Instability in Neuroendocrine Neoplasms
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Circulating Chromogranin A as a Surveillance Biomarker in Patients with Gastroenteropancreatic Neuroendocrine Tumours https://aacrjournals.org/clincancerres/article/30/24/5559/750428/Circulating-Chromogranin-A-as-a-SurveillanceCancer Network+2AACR Journals+2PLOS+2
Immune Checkpoint Markers in Neuroendocrine Carcinoma of the Digestive System
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The Prognostic and Predictive Role of Chromogranin A in Neuroendocrine Neoplasms
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