Researchers have found that patients with cancer who carry HLA-I alleles with high peptide-binding promiscuity have significantly worse prognosis after immune checkpoint inhibition.

The effect of generalist HLA molecules on the immune recognition of pathogens and tumours is that generalists make it possible for the immune system to recognise and destroy a higher number of pathogens.

However, there is a negative trade-off between the recognition of pathogens and tumours.

This study has recently been published in Nature Cancer.

HLA variants called generalists can bind and present a very large number of protein fragments to the immune system.

They present short protein fragments on the surface of cells and show extreme diversity resulting in large differences between individuals.

HLA molecules make it possible for the immune system to recognise the molecules of pathogens, tumours, and healthy cells.

Dr Máté Manczinger, lead author of the study, said “in our previous research, we showed that generalists make it possible for the immune system to recognise and destroy more pathogens.

This is explained by the low similarity between human and pathogen-associated proteins.

Consequently, in vain do generalists present more self-proteins, the immune system can easily distinguish pathogens from human cells.

In sum, in the case of generalist HLA molecules quantity predominates peptide presentation at the expense of quality, which results in the defective immune recognition of tumours.”

The human immune system plays a fundamental role in killing pathogens and tumours, while it is essential to tolerate healthy cells of the human body.

Tumour immunotherapy has revolutionised cancer treatment in the previous two decades.

The treatment is effective against advanced cancers and gave hope for patients in late disease stages.

Tumour immunotherapy augments the immune recognition of cancer cells, which could destroy even metastatic tumours.

Whilst immunotherapy is a huge step forward in the treatment of cancer patients, a notable fraction of them does not respond to the therapy.

Consequently, it is of utmost importance to identify biomarkers that can predict, which patients benefit from the treatment.

HLA variants are more prevalent in geographical regions with high pathogen diversity because they make it possible for the immune system to recognise more pathogens.

Dr Máté Manczinger notes “we would think that generalists are beneficial in terms of tumour recognition because they are more likely to bind and present the mutated protein fragments of cancer cells.

Surprisingly, we found the opposite. We focused on patients treated with immune checkpoint blockade immunotherapy.

We showed that although generalists are more likely to present mutated cancer peptides to the immune system, patients carrying generalist HLA variants have worse survival.”

The results from this study reveal the explanation for this phenomenon; generalists are not selective. They also bind and present the original peptides, from which mutated peptides arise.

As mutated and original peptides are often highly similar, the immune system is unable to distinguish between them and, thus it recognises tumour cells as healthy ones.

On the contrary, selective HLA variants are more likely to present only the mutated peptides and, thus, the immune system can recognise and destroy tumour cells more effectively.

The results from this study can help to decide, which patients should be treated with immune checkpoint blockade immunotherapy.

Importantly, adequate immune recognition of cancer is essential throughout life, which is exemplified by the increased susceptibility of immunocompromised individuals to cancer.

Dr Máté Manczinger explains, “we are planning to investigate whether individuals carrying generalist HLA molecules are generally predisposed to different tumours as their immune system are unable to recognise cancer cells effectively.”

Reference: Negative trade-off between neoantigen repertoire breadth and the specificity of HLA-I molecules shapes antitumor immunity