Most cancers biologists at EPFL, UNIGE, and the German Most cancers Analysis Heart (Heidelberg) have developed a novel immunotherapy that doesn’t require information of a tumor’s antigenic make-up. The brand new outcomes could pave the way in which to first-in-kind scientific purposes.
Sadly, tumors usually erect obstacles in opposition to the physique’s immune system, permitting them to develop uncontrolled. This setback, referred to as immunosuppression, could contain the inhibition of DCs and their capability to current tumor antigens to CD8+ T cells.
Addressing the constraints of conventional vaccines
Over the previous few a long time, researchers have labored to beat tumor-induced immunosuppression by numerous methods, collectively referred to as immunotherapies, a few of that are accredited therapies efficient in sufferers with sure cancers.
One method is to generate DCs from the blood monocytes (a kind of immune white blood cells) of a affected person with most cancers, expose them within the laboratory to outlined tumor-derived materials from a tumor biopsy (antigen loading step), after which reintroduce them into the affected person’s physique. This process, sometimes called a DC vaccine, is predicted to considerably improve the presentation of tumor antigens to CD8+ T cells.
Nevertheless, DC vaccines have produced combined ends in scientific trials. One potential limitation is using monocyte-derived DCs. These cells lack sure important properties of naturally occurring DCs, corresponding to sort I DCs (cDC1), which play a vital function in activating CD8+ T cells.
One other potential shortcoming is its dependence on the antigen loading step, which makes use of predefined antigens that will not symbolize the total spectrum of related antigens current in most cancers cells. Addressing the constraints of conventional DC vaccines might improve their therapeutic efficacy.
A staff of scientists led by Michele De Palma, affiliate professor within the Faculty of Life Sciences and director of the Agora Most cancers Analysis Heart, has now developed engineered DCs with the capability to distinguish into cDC1 and to stimulate anti-tumor immunity when transferred to mice with tumors, with out the necessity for antigen loading step. The research is printed in Nature Most cancers.
“Our technique doesn’t use the monocyte-derived DCs employed in earlier research, however depends on a inhabitants of DC progenitors, referred to as DCPs, which we are able to produce in vitro within the laboratory from available sources, corresponding to blood and bone marrow,” De Palma explains.
Surpassing the outcomes
When engineered to precise two immune-stimulatory molecules (IL-12 and FLT3L), the DCP might provoke efficient anti-tumor immune responses in numerous most cancers fashions, surpassing the outcomes achieved with different conventional DC formulations. “Remarkably, the engineered DCPs labored within the absence of antigen loading, which means that they might be probably efficient in opposition to a broad vary of human cancers, so no matter the antigens that they categorical.”
The flexibility of engineered DCPs to broadly interact a number of elements of the immune system, not restricted to CD8+ T cells, could clarify their effectiveness. “A really promising outcome was the power of the DCPs to unlock the efficacy of CAR-T cells in eradicating mind tumors in mice,” says Professor Denis Migliorini, head of neuro-oncology at UNIGE and one of many research’s authors.
CAR-T cells are one other class of engineered immune cells already accredited for the therapy of sure tumors, however their efficacy in mind most cancers has to date been restricted. “We’re dedicated to combining DCPs with CAR-T cells in sufferers with incurable mind most cancers,” provides Migliorini.
“Our preclinical outcomes require additional growth and testing earlier than transferring to scientific software,” cautions De Palma. DCPs may be readily obtained from human blood, which ought to facilitate the interpretation of preclinical outcomes right into a probably transformative most cancers immunotherapy.
Extra data: Ali Ghasemi et al, Cytokine-armed dendritic cell progenitors for antigen-agnostic most cancers immunotherapy, Nature Most cancers (2023). DOI: 10.1038/s43018-023-00668-y