In a recent study posted to the medRxiv* preprint server, a team of researchers explored the effect of immune checkpoint blockade (ICB)-induced expansion of age-associated B cells (ABCs) on coronavirus disease 2019 (COVID-19) vaccine-derived humoral immunity in patients with cancer and inborn errors of immunity (IEI).
Background
Immune checkpoint blockade is a cancer therapy that improves anti-cancer and anti-viral immunity by targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) checkpoints and consequently enhancing antibody responses by promoting T and B cell interactions. Observational studies have indicated better vaccine efficacy in cancer patients using ICB.
However, the benefits of using ICB to improve vaccine performance in cancer patients are confounded to a certain extent by the expansion of ABCs. Age-associated B cells are antigen-experienced B cells that expand and accumulate in healthy individuals, as the name suggests, with age. The natural accumulation of ABCs is beneficial for improved antibody responses because of their improved ability to present antigens to T cells. In people with immune disorders, infectious diseases, or autoimmunity, and sometimes as a response to the COVID-19 vaccine or infection, ABCs have been seen to accumulate prematurely.
In cancer patients, ICB therapy seems to cause the expansion of ABCs before either the antibody-mediated or the non-antibody-mediated immunity develops. Studies have found that this leads to a T cell deficit due to B-cell extrinsic functions in cancer patients and individuals with IEI. Therefore, understanding the effect of ICB-induced expansion of ABCs on the vaccine-related immune response is essential in decreasing the vulnerability of cancer and immune disorder patients to COVID-19.
About the study
In the present study, the researchers addressed two major questions — 1) are ABC levels in patients receiving ICB therapy similar to those in individuals not under ICB therapy? and 2) what effect does the expansion of ABCs during ICB therapy have on vaccination-related humoral responses?
To answer these questions, the team selected patients based on the deficient genes of interest, such as CTLA-4, lipopolysaccharide-responsive beige-like anchor protein (LRBA), and nuclear factor kappa B subunit 1 (NFκB1) and subunit 2 (NFκB2), and clinical diagnostics such as ICB therapy. A control group of healthy individuals was also included in the study. Blood samples from the participants, collected at different time points corresponding to the time of vaccination, were used for the study.
The researchers first used single-cell RNA sequencing (scRNAseq) to understand whether different transcriptional profiles were involved in ABCs arising from different etiologies. They investigated whether ABCs from different diseases or conditions could be subdivided based on the expression of different immune function genes, such as the autoimmune regulator (AIRE).
The second part of the study was a comprehensive longitudinal profile examining the response to the COVID-19 vaccination in all the participants. The profile included a serological assay to quantify antibodies specific to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein trimer. A neutralization assay measured antibody titers at 50% inhibition against wild-type SARS-CoV-2. Additionally, B cells were analyzed using flow cytometry.
Results
The study’s results indicate that while several factors, such as ageing, obesity, and polygenic risk alleles, can contribute to ABC expansion in older patients, the disruption of specific genes is responsible for the expansion of ABCs in younger patients suffering from rare inherited monogenic diseases.
The study found the ABC differentiation states to be homogenous across different groups consisting of cancer patients receiving ICB therapy, patients with CTLA4 or NFκB1 haploinsufficiency, systemic lupus erythematosus patients, as well as healthy individuals. These results suggest that it is the increased frequency of expanded ABCs which is responsible for its pathology and not inherent differences in the ABCs from patients with distinct diseases.
The most clinically relevant finding, however, was that patients with expanded ABCs exhibited a lower B cell response to the COVID-19 vaccine, which subsequently resulted in a decreased neutralization capacity and reduced formation of memory B cells. The memory B cell frequency indicates subsequent neutralization responses to booster vaccinations. Therefore, the results suggest that patients with cancers and immune dyscrasias will require frequent booster vaccines to maintain their B-cell-related immunity.
Conclusions
Overall, the study indicated that expansion of ABCs in IEI patients or cancer patients receiving ICB therapy results in a decrease in memory B cells, which reduces the duration and strength of vaccine-induced antibody responses. The authors believe that ABC expansion can be used as a biomarker for monitoring humoral immunity and administering booster doses of COVID-19 vaccinations in cancer patients.
*Important notice
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information
