New immunotherapies targeting the key purinergic checkpoints in the tumor microenvironment
Background: ATP and adenosine are constituents of the tumor microenvironment (TME). Extracellular ATP (eATP) promotes tumor growth but also immune-mediated tumor eradication, mainly via its cognate receptor P2X7R. Adenosine, generated from eATP via the CD39 and CD73 ectonucleotidases, is an immune suppressant acting at the A2A receptor (A2AR). The Purinergic checkpoints (PCs: P2X7R, CD39, CD73 and A2AR) mold TME immune responses. The therapeutic potential of their combined targeting is unknown. Pur-Ther partners generated PC-specific nanobodies and a probe (pmeLUC) that allows in vivo measurement of eATP. Hypothesis: We hypothesize that PC- and eATP-targeting will establish the basis for an innovative therapy for lung adenocarcinoma (LUAD) glioblastoma (GBM) and multiple myeloma (MM). Pur-Ther primary aims will be: A) investigate the expression, distribution and function of PCs in LUAD, GBM and MM, and B) validate anti-cancer therapies based on combining nanobody-based targeting of PCs with the targeting of canonical immune checkpoints. The secondary aims will be: A) develop novel probes for the in vivo investigation of TME e ATP; B) develop tumor-selective multispecific nanobodies and pmeLUC-nanobody fusion proteins for in vivo measurement of TME eATP; C) preclinically validate these proteins as therapeutic and diagnostic tools. Methods: Expression and function of PCs, and their interaction with canonical immune checkpoints (e.g. PD-1 and PD-L1) will be investigated in tumor human samples and mouse models. PC mapping will be achieved by digital spatial profiling and NGS. In vivo TME eATP will be investigated by total body luminometry. Human tumor organoids will be used for in vitro testing. Expected results: We anticipate to develop novel cancer therapies based on the combined targeting of purinergic and immune checkpoints. Potential impact: We expect that this novel combined approach will improve and extend the application range of current immune-checkpoint-based therapies. We are confident that our efforts will pave the way to the definition of novel and effective anti-cancer therapeutic protocols.
Funded by the European Union under the Horizon Europe Framework Programme - Grant Agreement Nº: 101095654. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or European Health and Digital Executive Agency (HADEA). Neither the European Union nor the granting authority can be held responsible for them.