Optimisation of anti-cancer peptide vaccines to preferentially elicit high-avidity T cells.

Therapeutic cancer vaccines often do not substantially reduce tumour burden, despite stimulating anti-tumour cytotoxic T lymphocytes (CTLs). Recent experiments have shown that the majority of vaccine-elicited CTLs may be of low-avidity. Moreover, low-avidity CTLs, which are abundant, do not kill cancer cells and potentially inhibit the ability of high-avidity T cells to kill cancer cells. By modelling CTL selection using a system of ordinary differential equations, we show that the efficacy of the peptide vaccine may be improved by controlling its delivery and dosage to preferentially elicit high-avidity CTLs. Our simulations predict that weekly, reduced doses of a vaccine may result in a greater than 90% reduction in cancer concentration. By contrast, a standard vaccine protocol such as a high-dose injection given every 2 weeks induces only a 65% reduction. Our model demonstrates a proof-of-concept approach to targeting immune responses for CTL selection, thereby offering a technique to potentially improve existing therapies.

Discovery of disease-adapted bacterial lineages in inflammatory bowel diseases.

Gut bacteria are implicated in inflammatory bowel disease (IBD), but the strains driving these associations are unknown. Large-scale studies of microbiome evolution could reveal the imprint of disease on gut bacteria, thus pinpointing the strains and genes that may underlie inflammation. Here, we use stool metagenomes of thousands of IBD patients and healthy controls to reconstruct 140,000 strain genotypes, revealing hundreds of lineages enriched in IBD. We demonstrate that these strains are ancient, taxonomically diverse, and ubiquitous in humans. Moreover, disease-associated strains outcompete their healthy counterparts during inflammation, implying long-term adaptation to disease. Strain genetic differences map onto known axes of inflammation, including oxidative stress, nutrient biosynthesis, and immune evasion. Lastly, the loss of health-associated strains of Eggerthella lenta was predictive of fecal calprotectin, a biomarker of disease severity. Our work identifies reservoirs of strain diversity that may impact inflammatory disease and can be extended to other microbiome-associated diseases.

A minimal model of T cell avidity may identify subtherapeutic vaccine schedules.

T cells protect the body from cancer by recognising tumour-associated antigens. Recognising these antigens depends on multiple factors, one of which is T cell avidity, i.e., the total interaction strength between a T cell and a cancer cell. While both high- and low-avidity T cells can kill cancer cells, durable anti-cancer immune responses require the selection of high-avidity T cells. Previous experimentation with anti-cancer vaccines, however, has shown that most vaccines elicit low-avidity T cells. Optimising vaccine schedules may remedy this by preferentially selecting high-avidity T cells. Here, we use mathematical modelling to develop a simple, phenomenological model of avidity selection that may identify vaccine schedules that disproportionately favour low-avidity T cells. We calibrate our model to our prior, more complex model, and then validate it against several experimental data sets. We find that the sensitivity of the model's parameters change with vaccine dosage, which allows us to use a patient's data and clinical history to screen for suitable vaccine strategies.

Mature Dendritic Cells May Promote High-Avidity Tuning of Vaccine T Cell Responses.

Therapeutic vaccines can elicit tumor-specific cytotoxic T lymphocytes (CTLs), but durable reductions in tumor burden require vaccines that stimulate high-avidity CTLs. Recent advances in immunotherapy responses have led to renewed interest in vaccine approaches, including dendritic cell vaccine strategies. However, dendritic cell requirements for vaccines that generate potent anti-tumor T-cell responses are unclear. Here we use mathematical modeling to show that, counterintuitively, increasing levels of immature dendritic cells may lead to selective expansion of high-avidity CTLs. This finding is in contrast with traditional dendritic cell vaccine approaches that have sought to harness ex vivo generated mature dendritic cells. We show that the injection of vaccine antigens in the context of increased numbers of immature dendritic cells results in a decreased overall peptide:MHC complex load that favors high-avidity CTL activation and expansion. Overall, our results provide a firm basis for further development of this approach, both alone and in combination with other immunotherapies such as checkpoint blockade.