Our latest research on next-generation anti-cancer vaccines against T cell-depleted tumors – Cell Stress and Immunity Lab
Cell Stress and Immunity Lab shared on X/Twitter:
“Thrilled to share our latest research on next-generation anti-cancer vaccines against T cell-depleted tumors! This helped discover a novel immunoresistance pathway mediated by PD-L1+ macrophages in mouse and patients!
We found that contrary to belief, clinical DC vaccines differentiate into 3 distinct molecular trajectories with contradictory clinical impact! Type I interferon markers distinguished the most immunogenic and clinically efficacious maturation state of human DC vaccines!
Inspired by our cancer patient data, we designed a novel DC vaccine with immunogenic trajectory i.e., DCvax-IT! DCvax-IT co-integrated immunogenic cancer cell death (ICD) and IFNβ stimulation that favored type I IFN responses over macrophage-like or mregDC trajectories!
Confirmatively, type I IFN response distinguished the most immunogenic DC vaccine in vivo, and accordingly our DCvax-IT therapy induced type I IFN sensing-dependent anticancer immunity in vivo
BUT…
to our surprise, curative DCvax-IT failed against T cell-depleted tumors!
Curative failure of DCvax-IT set us onto a detective task! We found that T cell-depleted tumors accumulated anti-inflammatory PD-L1+ macrophages that supressed CD8+T cells via TRAIL signaling! Accordingly, PD-L1 blockade reduced accumulation of PD-L1+ macrophages!
In line with these immuno-resistance insights, combination of DCvax-IT & PD-L1 blockade together suppressed T cell-depleted tumors by overcoming PD-L1+ macrophages.
SURPRISINGLY…
We saw that in fact DCvax-IT themselves were inducing PD-L1+ macrophages in lymph nodes!
DCvax-IT also mobilized PD-L1+ macrophages in tumours such that DCvax-IT combo with PD-L1 blockade was necessary to blunt these macrophages in both lymph node and tumours to promote anticancer T cells! >>> DC-derived IFNs and tumoural IFN-gamma created these macrophages.
Importantly, PD-L1 and macrophage co-association created a negative prognostic niche in human cancers that predicted clinical responses to PD-L1 blockade!!
REMARKABLY…
Clinical DC vaccines also mobilized T cell-suppressive PD-L1+ macrophages in glioblastoma patients!
Conclusion: We used human-to-mouse reverse translation to create DC vaccines. Counterintuitively, these induced T cell-suppressive PDL1+macrophages in lymph nodes/tumors! This pathway was also present in patients. Vaccination and PD-L1 blockade was mandatory to blunt tumors.
This brilliant Cell Reports Medicine paper was made possible because of a series of collaborators and our lab mates, especially the lead author Jenny Sprooten! Thanks also to off-twitter collaborators, as well as Stefan Naulaerts, Jannes Govaerts, Sabine Tejpar, Steven De Vleeschouwer!
Thanks also to all our funders, sponsors and supporters: KU Leuven, The Scientific Research Fund – Flanders (FWO), UZ Leuven, Leuven Kankerinstituut, Stand Up Against Cancer!”
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Source: Cell Stress and Immunity Lab/X