Unleashing the potential of immunity for early cancer detection

While there have been notable improvements in cancer treatment, the mortality rate remains high for individuals diagnosed at later stages of disease.

This persistent challenge has sparked a surge in research efforts to improve patient outcomes by enhancing early cancer detection. Pioneering programmes such as the International Alliance for Cancer Early Detection (ACED) exemplify this commitment, offering hope for a future where the majority of cancers can be identified at a treatable, if not curative, stage.

The implementation of screening programmes for numerous cancer types is playing a crucial role in addressing this problem by detecting diseases early in asymptomatic individuals. However, this approach is not without its hurdles. Poor sensitivity, restrictive eligibility criteria, a socioeconomic disparity in screening accessibility, low participation rates for invasive procedures, detection of inconsequential disease, and a substantial burden on resources such as imaging equipment all play a role in making this a difficult challenge.

A very promising step forward has been the emergence of ‘liquid biopsies’, as a tool for the future. This approach tackles many of the issues with screening, offering promise as an accessible and cost-effective alternative to current techniques.

Much of the focus in this arena has centred on genomic techniques such as detecting cell-free tumour DNA (ctDNA), which is released into the bloodstream when tumour cells circulate and die, leaving a traceable signal in blood plasma. This approach has been extremely impactful, with the large-scale NHS-Galleri trial currently testing a ctDNA test for asymptomatic individuals across multiple cancer types. Interim reports from Galleri suggest limitations of this test in sensitivity for early-stage disease, with a tendency to detect micrometastatic disease and hard-to-treat tumours. This potentially limits clinical utility as it could miss cases that don’t fall into these categories – often the case with early-stage tumours.

The absence of a standardised, powerful, non-invasive early detection test has paved the way for intense exploration of alternative biological pathways that may suit early detection. To this end, we and others have begun to consider the potential to exploit the immune system.

Leveraging immunity for detection

The role of the immune system in anti-cancer immunity is supported by an immense and growing set of data, perhaps most notably the remarkable success of immune checkpoint inhibitor therapy.

In recent years, increasingly high-quality evidence has demonstrated that the immune system actively engages in the ‘three Es’ of immunoediting upon encountering malignancy.

Firstly, the immune system conducts surveillance to detect ‘non-self’ signals generated by both established and developing tumours. The immune system is therefore activated very early as a cancer develops as it mounts an attempt to eliminate these aberrant cells before a full-blown malignancy can emerge.

In some cases, cancer cells may enter a state of equilibrium with the immune system, preventing further growth. Should this defensive mechanism prove insufficient, or if it fails altogether, the rogue tumour cells escape detection and progress into a cancer.

Humans represent a patchwork of somatic mutations in normal clonally expanded cell populations – generated by exposures such as UV and tobacco – and whether these are subject to immunosurveillance remains unaddressed. Given that we already employ immune monitoring in various clinical contexts such as infection and transplantation, it prompts the intriguing question: can we leverage this exquisitely sensitive intrinsic system for the early detection of cancer?

Knowledge gap

The human immune system operates through two primary branches: Innate immunity, swiftly responding to immediate threats, and adaptive immunity, employing immune memory to address recurrent challenges. Each of these is characterised by discernible signals, for example inflammation markers signalling an innate response, and antibodies indicating an adaptive response.

For early detection, the key to unlocking the full potential of this intricate system will be to address some as yet unanswered questions.

Firstly, which immune processes are activated early in tumour development? It’s of course possible to posit theories based on knowledge of general immunology, the setting of cancer poses a new challenge and is likely to be dynamic and complex. In the sequence of events that unfold as our immune system confronts a developing tumour, we can reasonably expect the innate immune system to take the lead. Always useful here I think to remind ourselves these are the first responders, with natural killer cells and macrophages playing key roles.

The subsequent step would involve antigen presentation. Cells such as dendritic cells capture and showcase tumour-specific antigens, signalling the adaptive immune system ‘detectives’ to come into play and use T and B cells to target tumour cells with precision. This response involves tissue resident cells, as well as cells residing in secondary and tertiary immune structures such as lymph nodes. However, it’s worth noting that the effectiveness of this response may be impaired by the limited availability of antigens, especially in the context of a preinvasive lesion or very early-stage tumour.

Secondly, which measurable signals are produced? Inflammation represents a hallmark of a developing tumour, but the signals produced by this process can be noisy and non-specific. Discerning a cancer-specific set of inflammation markers will be crucial.

Certain aspects of adaptive immunity, such as antibody production, are well-documented in the early phases of cancer. Moreover, emerging evidence suggests the early engagement of a T cell response, measurable through features like T cell receptor repertoires. Investigating and refining both of these adaptive signals is imperative to establish a benchmark for identifying cancer, as they hold the potential to be exceptionally specific.

To do this though, we must contend with the potential influence of confounding factors in the population – think infections, recent vaccinations and chronic inflammation triggered by co-existing conditions.

Designing a test for widespread application demands an astute ability to navigate this real-world complexity, distinguishing with precision between signals associated with cancer immunity and those stemming from unrelated sources.

Finding that all-important signature

With support from CRUK, as well as collaboration with a team from The Royal Marsden NHS Foundation Trust led by Dr Richard Lee, Consultant Physician in Respiratory Medicine and Champion for Early Cancer Diagnosis, my PhD project aims to design a multi-parametric immunopredictor of early-stage cancer.

The power of this approach is the ability to integrate immune signals that, individually, might lack the sensitivity to meet diagnostic thresholds. However, collectively, they hold the potential to form a composite signature capable of differentiating between patients with cancer and those who are healthy.

Our specific focus is on three key components of the anti-cancer immune response: cytokines, antibodies, and T cell receptors. These components collectively represent the essential facets of the immune system, enabling a comprehensive exploration to identify the most important signals and pathways crucial for cancer detection.

A key challenge to early-stage cancer research is the scarcity of samples which truly represent the earliest stages of disease. To this end, we are actively curating a unique cohort of patients with indeterminate lung nodules that may represent early lung cancer as part of the Nodule Immunophenotyping Biomarker for Early Lung Cancer Diagnosis (NIMBLE) study.

NIMBLE is run through the Early Diagnosis and Detection Centre at The Royal Marsden and the Institute of Cancer Research – supported by The Royal Marsden Cancer Charity and the National Institute for Health and Care Research. It is the first prospective lung cancer study with immune analysis as the primary endpoint. We are working with fourteen hospital sites across the UK to recruit 500 patients with up to two follow-up timepoints each, and we collect viable immune cells, plasma, and germline DNA from each sample.

We are therefore extremely fortunate to be able to assess differences between cancerous and benign conditions in a real-world setting. Our diverse cohort spans a range of ages and encompasses individuals with a spectrum of environmental carcinogenic exposure, providing a rich and authentic backdrop for our investigations.

Translation goals

The rapidly growing interest in cancer immunity stems from a deeper understanding of immunology than ever before, and a desire to think innovatively to improve current cancer care.

Our ultimate aim is to produce a tool with high translational impact, whether this be complementary to ctDNA to improve sensitivity and specificity, or as a standalone diagnostic.

We are extremely grateful to all the research teams and patients who are supporting this work. To all those in it, and we hope a few outside, this is a hugely exciting field, and we hope that immune monitoring will become standard practise in the future to enable a better quality of life and more positive outcomes for cancer patients.