Publication highlights

Scientists from the Crick, UCL, UCLH and Personalis have found that a test to detect circulating tumour DNA can predict lung cancer outcome in a Cancer Research UK-funded study. The researchers tested a platform called NeXT Personal, which can detect very small amounts – 1 part per million – of ctDNA (fragments of DNA released into the blood by tumours). They applied the platform to blood plasma samples from 171 people with early-stage lung cancer in the TRACERx cohort, finding that people with a low level of ctDNA before surgery were less likely to relapse and had improved overall survival rates than people with a high level of ctDNA. The high sensitivity of the test meant that smaller amounts of ctDNA could be detected, which prevented people with a lower amount of ctDNA from being incorrectly labelled ctDNA negative.

Researchers in the Cancer Evolution and Genome Instability Laboratory at the Crick and at UCL have developed a tool, MHC Hammer, to study genetic mutations and transcriptional alterations in HLA genes that help cancer cells evade the immune system. HLA molecules present "neoantigens" that signal the immune system to attack. Mutations and transcriptional alterations in these genes can prevent neoantigen presentation by disrupting the HLA molecule, allowing cancer cells to hide. The tool identified four types of HLA disruption in lung and breast cancer that could result in fewer neoantigens on tumour cells. One type - loss of one copy of an HLA gene - was associated with metastasis. Epigenetic changes, like increased methylation, may also reduce HLA expression in cancer cells.

Researchers at the Francis Crick Institute, UCL and AstraZeneca have discovered the reason why targeted treatment for non-small cell lung cancer fails to work for some patients, particularly those who have never smoked. The study shows that lung cancer cells with two particular genetic mutations are more likely to double their genome, which helps them to withstand treatment and develop resistance to it. The researchers re-analysed data from the trials of a new EGFR inhibitor, which blocks a common genetic mutation in this type of lung cancer. They compared the impact of treatment for patients with either EGFR-only or with EGFR and p53 mutations, finding that tumours got smaller in response to treatment for patients with just EGFR mutations. But for patients with both mutations, some tumours had grown, providing evidence of rapid drug resistance. This was confirmed in mice with both mutations - resistant cells had doubled their genomes.

Does infection or vaccination induce nasal neutralising antibodies to SARS-CoV-2 variants? The Covid Surveillance Unit has developed a fast, easy method to test if antibodies in nasal mucosa stop SARS-CoV-2 replicating in cells in swabs from participants in the UCLH-Crick Legacy study. Both vaccination and infection boosted antibody levels in nasal mucus, and repeated vaccinations could enhance this. Importantly, the range of nasal antibodies differs from that in blood, which means current vaccines may not stop infections with new antigenically different variants. The methodology used in the study will make it easy to evaluate next generation vaccines, including mucosal vaccines.

In the UCLH-Crick Legacy study, the team asked why the UK didn't experience the predicted severe COVID wave from Omicron “escape variants” XBB and B.Q.1.1 (variants which arise from weaker immune responses to the vaccine) in winter 2022, unlike Singapore and the US. They used serum collected from Legacy study volunteers and tested for neutralising antibodies against these “escape variants” before and after the bilvalent vaccine - a type of vaccine which targets the original strain and Omicron strain.

Using data from the COVID Surveillance Unit’s specialist antibody tests against variants XBB, XBB.1.5 and BQ.1.1, they found that neutralising antibodies against these variants were boosted 3-4-fold in all participants after the bivalent vaccine. They also found any prior infection was a major contributor to high levels of neutralising antibodies against these new variants, but participants who hadn’t been infected still had neutralising antibodies against XBB after vaccination. Any 4th “encounter” with another Omicron variant, Spike, in 2022, boosted antibodies against these variants in patients who had had three vaccines. People who had been infected with the BA.1/2/5 variant had similar levels of antibodies as those who had been given the 4th vaccine. In summary, the UK’s targeted 4th dose vaccine policy by JCVI complemented widespread existing hybrid immunity in the wider UK population, protecting against the predicted severe wave of COVID-19 in UK winter 2022-3.

Endogenous retroviruses (ERVs) are a specific group of viruses that altered human evolution by inserting themselves into our DNA. Often these alterations do not cause any changes in human health and disease, however in some cases they may impact the way a disease progresses by changing the way our genes function. This happens because ERVs can help to generate new versions of proteins. In this paper, the aim was to explore whether the calcium regulatory protein calbindin influenced lung cancer cells when present in the ERV-altered form (ERV-calbindin).

Lung cancer cell growth and inflammation was compared in the presence and absence of ERV-calbindin. The results indicated that ERV-calbindin aided lung cancer cell survival and tumour-promoting inflammation. On the other hand, ERV-calbindin deficient lung cancer cells grew slower, initiated the recruitment of immune cells called neutrophils and released the inflammatory marker interleukin-8. This creates an interplay between pro and anti-tumour immune reactions. Altogether the reduction in growth and increase in inflammation observed in the absence of ERV-calbindin is a phenomenon called “senescence”. These results imply that the presence of the ERV altered form of calbindin aids cancer cell growth and survival and could potentially pose as a future target for therapies.

Researchers in the Kassiotis lab have shown that a specific area of the SARS-CoV-2 spike protein is a promising target for a pan-coronavirus vaccine that could offer some protection against new virus variants, common colds, and help prepare for future pandemics.

As part of the CAPTURE study, researchers in collaboration with the National Institute for Health Research (NIHR) UCLH Biomedical Research Centre found that antibodies generated in people who had received only two doses of either the Oxford/AstraZeneca vaccine or the Pfizer/BioNTech vaccine were less able to neutralise the Omicron variant as compared to the Alpha and Delta variants. They also found that antibody levels dropped off in the first three months following the second dose but that a third ‘booster’ dose raised levels of antibodies that effectively neutralise the Omicron variant.

As part of the largest study to comprehensively evaluate the response of patients with cancer to COVID-19 vaccines, researchers in the Turajlic lab monitored the immune response of 585 patients with different types of cancer after receiving a first and second dose of the COVID-19 vaccine.
They found that patients with blood cancer were less likely to have antibodies than individuals of a similar age without cancer or with solid cancer, and when they did have antibodies, the levels were lower against all variants.

Two doses of the Oxford-AstraZeneca COVID-19 vaccine induce lower levels of antibodies that are able to recognise and fight the SARS-CoV-2 Delta variant (B.1.617.2) than against other strains.

The Legacy study team found that two doses of the Oxford-AstraZeneca vaccine generate lower levels of antibodies able to recognise the Delta variant, in comparison with the Pfizer-BioNTech vaccine. Their results also show that antibody levels vary considerably depending on likely prior infection with SARS-CoV-2.