A small-molecule P2RX7 activator promotes anti-tumor immune responses and sensitizes lung tumor to immunotherapy

Abstract

Only a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop therapeutic strategies to improve patient outcome. We develop a chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates αPD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7-expressing cells to generate IL-18 which leads to the production of IFN-γ by Natural Killer and CD4+ T cells within tumors. Combined with immune checkpoint inhibitor, the molecule induces a complete tumor regression in 80% of LLC tumor-bearing mice. Cured mice are also protected against tumor re-challenge due to a CD8-dependent protective response. Hence, combination treatment of small-molecule P2RX7 activator followed by immune checkpoint inhibitor represents a strategy that may be active against NSCLC.

ATP and cancer immunosurveillance

“…This agent is currently being tested in combination with the immune checkpoint inhibitor (ICI) atezolizumab (a PD‐L1‐blocking antibody) for safety and preliminary efficacy in a phase I clinical trial enrolling patients with solid tumors (JapicCTI‐205153). Along similar lines, it has recently been shown that a novel positive allosteric modulator of P2RX7 (which only acts in the presence of high extracellular ATP levels) potentiates the therapeutic effects of an ICI specific for programmed cell death 1 (PDCD1, best known as PD‐1) by stimulating DCs to release IL18 in support of the effector functions of tumor‐infiltrating NK cells and CTLs (Douguet et al , 2021). Incidentally, these therapeutic applications provide an independent and convincing demonstration (mutatis mutandis, almost an “ex adiuvantibus” proof) of the accuracy of early measurements of extracellular ATP concentration in the TME (Pellegatti et al , 2008).…”

P2X7: a receptor with a split personality that raises new hopes for anti-cancer therapy

“…In a recent paper, Valerie Vouret-Craviari and coworkers show that controlled activation of the P2X7 receptor (P2X7R) inhibits growth of non-small cell lung cancer (NSCLC), promotes tumor regression in association with anti-PD-1 antibodies, and confers long-lasting CD8 + lymphocyte-mediated immunity [ 1 ]. The pathophysiological function of the P2X7 receptor (P2X7R) is still a puzzle 25 years after its cloning [ 2 ] and even longer since its role in immunity and cancer was first postulated [ 3 ] [ 4 ] [ 5 ].…”

“…The trick to achieving tumor selectivity was to engineer an antibody that binds the cognate target (the CD137 receptor of NK cells) only in the presence of near-millimolar eATP concentrations. Valerie Vouret-Craviari and her coworkers in their recent paper took a further step forward by exploiting eATP in the TME together with P2X7R pharmacology [ 1 ].…”

“…However, several positive allosteric modulators, i.e., molecules that activate the P2X7R only in the presence of eATP, presumably acting at sites different from the nucleotide-binding site, have been identified over the years [ 24 ] [ 25 ]. Thus, Vouret-Craviari and coworkers had the clever idea of verifying whether a novel P2X7R-positive allosteric modulator (HEI3090) might trigger a controlled activation of the P2X7R in the high eATP TME and thus achieve tumor elimination [ 1 ]. To set up a more thorough anti-cancer strategy, these authors combined HEI3090 treatment with αPD-1 immune check-point antibodies.…”

“…While small cation flux is in principle associated with the activation of trophic functions, unrestricted passage of larger solutes dramatically upsets intracellular ion balance and initiates a death (necrosis, apoptosis, or pyroptosis) pathway. Indirect evidence suggests that the P2X7R might undergo a “controlled” activation, leading to opening of the ion channel, but not of the large conductance pore, but until the report of Vouret-Craviari and coworkers [ 1 ], there was no in vivo evidence that pharmacological treatment could achieve this goal. Some hints of controlled P2X7R activation come from the discovery of P2X7R-positive allosteric modulators [ 24 ] [ 25 ].…”