Paul Ehrlich’s Hypothesis on the Immune System and Cancer

Historical Context

Paul Ehrlich, a prominent Jewish physician and scientist in the late 19th century, proposed a groundbreaking hypothesis regarding the immune system’s role in cancer prevention. He suggested that the immune system actively surveys the body for early tumour cells, destroying them before they can develop into cancer. Despite being largely overlooked for decades, recent research indicates that Ehrlich’s ideas may have merit.

Understanding Tumour Growth

Benign tumours represent cancerous masses that can grow uncontrollably within the body. As these tumours progress, genetic mutations occur in some of their cells, potentially leading to new, more aggressive cancerous traits, such as resistance to chemotherapy. Current studies reveal that immune cells are not only persistently infiltrating tumours to suppress and eliminate them, but also that the epigenetics of these immune cells can change as the tumour evolves.

Recent Research on DNA Methylation and Cancer

Study Overview

A multinational team of researchers from China, Canada, and Sweden conducted a study to explore the potential of DNA methylation as a diagnostic tool for cancer. Their findings were published in the journal Clinical Epigenetics, focusing specifically on how immune cells in peripheral blood change their epigenetics during the progression of hepatocellular carcinoma (HCC).

Understanding Genetics and Epigenetics

Genetics examines the essential genes involved in growth, development, and bodily functions, while epigenetics studies how these genes are regulated over a person’s lifetime. This study particularly targeted CpG islands—specific DNA regions that can be modified through methylation, a biochemical process that can deactivate certain genes.

Methodology

The researchers collected whole blood samples from HCC patients at various stages, alongside patients with hepatitis B or C, and healthy controls. They analyzed the DNA from these samples for patterns of DNA methylation.

Findings on DNA Methylation Patterns

Correlation with HCC Progression

The analysis of DNA methylation patterns revealed a significant correlation with HCC progression. Early-stage HCC patients exhibited high levels of DNA hypermethylation, whereas those in later stages displayed low levels of DNA hypomethylation. When compared to samples from hepatitis patients, the methylation patterns of HCC patients were more similar to each other, indicating that these patterns may result from cancer rather than other illnesses.

Impact on Gene Regulation

Given that DNA methylation controls gene expression, the researchers identified which genes were demethylated and consequently silenced as HCC advanced. They found a linear relationship between the methylation of immune-related gene regulators and HCC progression, suggesting that cancer modifies immune cell epigenetics and behavior.

PD-1 Gene Findings

Notably, the promoter region of the PD-1 gene—a critical immune checkpoint—was found to be demethylated in advanced HCC stages. Since an active PD-1 gene inhibits immune cell function, this indicates that immune cell activity diminishes as HCC progresses, contributing to the severity and lethality associated with late-stage cancers.

Implications for Early Diagnosis

Using DNA Methylation as a Biomarker

Early diagnosis of HCC is crucial for improving treatment outcomes and survival rates. Recognizing the correlation between HCC progression and DNA hypomethylation in peripheral blood, the researchers sought to determine if gene methylation status could serve as a biomarker for HCC diagnosis across all stages.

Key Findings on STAP1 Gene

Utilizing T cell and peripheral blood epigenome data, the researchers identified the STAP1 gene as a promising biomarker, demonstrating an accuracy of 85.7% in diagnosing early-stage HCC compared to hepatitis and healthy controls.

Significance of the Study

This research underscores the essential role of DNA methylation in regulating the epigenome and immune cell behavior. The study revealed that as HCC progresses, there is a significant decline in methylation within immune cells, particularly affecting genes associated with immune functions. The hypomethylation of the PD-1 gene suggests it may be activated, leading to immune suppression, thus indicating a potential target for therapeutic intervention in late-stage HCC patients.

The study’s findings also pave the way for future advancements in using peripheral blood for early-stage HCC diagnosis, potentially facilitating the development of accessible blood tests to detect cancers that are currently difficult to identify in their initial stages. These results highlight the promise of DNA methylation as a tool for both therapeutic and diagnostic applications in cancer research.

Reference

Zhang, Y. et al. The signature of liver cancer in immune cells DNA methylation. 1–17 (2018). doi:10.1186/s13148-017-0436-1