Why does immunotherapy not work in some cancer patients?

The human leukocyte antigen (HLA) complex is an important part of our immune system. Controlled by genes located on human chromosome 6, it encodes cell-surface proteins that play key roles in the generation of immune responses.

HLA genes are highly polymorphic, with a wide variety of alleles – variant forms of a gene – helping them fine-tune the immune system. HLA-I genes shape our body’s immune response to pathogens and cancer, their main role being to present peptide antigens to the immune system for destruction. It’s known that some HLA-I alleles act as generalists and can bind a wider range of peptides than others, potentially helping to fight many viral diseases. But how does this affect the immune response to cancer?

Researchers supported by the EU-funded resistance evolution and HCEMM projects have now discovered that cancer patients with HLA-I alleles that bind to a wide range of peptides have a significantly worse prognosis after immune checkpoint inhibition. Their findings were published in the journal ‘Nature Cancer’.

“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,” observed study lead author Dr Máté Manczinger of the Biological Research Centre, Hungary, in a news item posted on ‘ecancer’. “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.”Checkpoint proteins keep immune responses in check, preventing them from being so strong that they kill healthy cells. Sometimes, when proteins on the surface of immune T cells bind to partner proteins on cancer cells, they send an ‘off’ signal to the T cells, stopping them from killing the cancer cells. Immunotherapy drugs called immune checkpoint inhibitors prevent such checkpoint proteins from binding with their partner proteins. The off signal isn’t sent, allowing the T cells to kill the cancer cells.

However, many cancer patients don’t respond to immunotherapy. Identifying biomarkers that can predict which patients benefit from this treatment is therefore crucial. “[W]e 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,” noted Dr Manczinger.

The reason is that generalists aren’t selective, presenting self-peptides as well as cancer mutation-derived peptides to the immune system. Unable to tell the two apart, the immune system identifies the cancer cells as healthy ones. The next step for the researchers supported by the resistance evolution (Bacterial evolution of hypersensitivity and resistance against antimicrobial peptides) and HCEMM (Establishing the Hungarian Center of Excellence for Molecular Medicine in partnership with EMBL) projects is “to investigate whether individuals carrying generalist HLA molecules are generally predisposed to different tumours.”

For more information, please see:

resistance evolution project

HCEMM project website