Most cancers biologists at EPFL, UNIGE, and the German Most cancers Analysis Heart (Heidelberg) have developed a novel immunotherapy that doesn’t require data of a tumor’s antigenic make-up. The brand new outcomes could pave the way in which to first-in-kind medical functions.
Sadly, tumors usually erect limitations towards the physique’s immune system, permitting them to develop uncontrolled. This setback, known as immunosuppression, could contain the inhibition of DCs and their skill to current tumor antigens to CD8+ T cells.
Addressing the restrictions of conventional vaccines
Over the previous few a long time, researchers have labored to beat tumor-induced immunosuppression by numerous methods, collectively known as immunotherapies, a few of that are accredited remedies efficient in sufferers with sure cancers.
One strategy 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, also known as a DC vaccine, is predicted to considerably improve the presentation of tumor antigens to CD8+ T cells.
Nonetheless, DC vaccines have produced blended ends in medical trials. One potential limitation is using monocyte-derived DCs. These cells lack sure important properties of naturally occurring DCs, similar 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 characterize the complete spectrum of related antigens current in most cancers cells. Addressing the restrictions of conventional DC vaccines might improve their therapeutic efficacy.
A crew 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 revealed 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, known as DCPs, which we will produce in vitro within the laboratory from available sources, similar 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 doubtlessly efficient towards a broad vary of human cancers, so no matter the antigens that they specific.”
The power 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 flexibility 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 remedy of sure tumors, however their efficacy in mind most cancers has thus far 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 shifting to medical utility,” cautions De Palma. DCPs will be readily obtained from human blood, which ought to facilitate the interpretation of preclinical outcomes right into a doubtlessly 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