The adenosine pathway in immuno-oncology

Allard, Bertrand; Allard, David; Buisseret, Laurence; Stagg, John

doi:10.1038/s41571-020-0382-2

Cited by 358 publications

(337 citation statements)

References 233 publications

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“…We next tested whether immunosuppressive features of the myeloid immune infiltrate would correlate with VISTA levels in this patient subset. We found that VSIR levels correlate (to variable degrees) with the abundance of TGFB1 and IL10 (coding for two cytokines with robust immunosuppressive activity), ENTPD1 and 4NTE (which code for two ectonucleotidases involved in the generation of the immunoregulatory metabolite adenosine), 55 , 56 IDO1 (encoding an intracellular enzyme involved in the degradation of tryptophan, which is required for optimal T cell activity, and the synthesis of kynurenine, which is immunosuppressive) 57 , 58 as well as CD38 (which codes for another extracellular enzyme with immunoregulatory activity) 59 ( Figure 4(f )). In line with this notion, VSIR high TNBCs significantly differed from their VSIR low counterparts in the relative abundance of each of these transcripts taken individually and in association, conveying a global signature of myeloid immunosuppression ( Figure 4(g )).…”

Section: Resultsmentioning

confidence: 96%

Converging focal radiation and immunotherapy in a preclinical model of triple negative breast cancer: contribution of VISTA blockade

et al. 2020

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Antibodies targeting the co-inhibitory receptor programmed cell death 1 (PDCD1, best known as PD-1) or its main ligand CD274 (best known as PD-L1) have shown some activity in patients with metastatic triple-negative breast cancer (TNBC), especially in a recent Phase III clinical trial combining PD-L1 blockade with taxane-based chemotherapy. Despite these encouraging findings, however, most patients with TNBC fail to derive significant benefits from PD-L1 blockade, calling for the identification of novel therapeutic approaches. Here, we used the 4T1 murine mammary cancer model of metastatic and immune-resistant TNBC to test whether focal radiation therapy (RT), a powerful inducer of immunogenic cell death, in combination with various immunotherapeutic strategies can overcome resistance to immune checkpoint blockade. Our results suggest that focal RT enhances the therapeutic effects of PD-1 blockade against primary 4T1 tumors and their metastases. Similarly, the efficacy of an antibody specific for V-set immunoregulatory receptor (VSIR, another co-inhibitory receptor best known as VISTA) was enhanced by focal RT. Administration of cyclophosphamide plus RT and dual PD-1/VISTA blockade had superior therapeutic effects, which were associated with activation of tumor-infiltrating CD8 + T cells and depletion of intratumoral granulocytic myeloid-derived suppressor cells (MDSCs). Overall, these results demonstrate that RT can sensitize immunorefractory tumors to VISTA or PD-1 blockade, that this effect is enhanced by the addition of cyclophosphamide and suggest that a multipronged immunotherapeutic approach may also be required to increase the incidence of durable responses in patients with TNBC.

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Section: Resultsmentioning

confidence: 96%

Converging focal radiation and immunotherapy in a preclinical model of triple negative breast cancer: contribution of VISTA blockade

et al. 2020

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“…In addition to PD-1 and CTLA-4, numerous other immune checkpoints have been shown to stimulate anti-tumor immunity. Amongst the next generation of immune checkpoint inhibitors are mAbs targeting the CD73 ecto-nucleotidases responsible for the generation of extracellular and immunosuppressive adenosine [4,5].…”

Section: Ivyspringmentioning

confidence: 99%

The effect of ultrasound pulse length on microbubble cavitation induced antibody accumulation and distribution in a mouse model of breast cancer

Amate¹,

Goldgewicht

Sellamuthu³

et al. 2020

Nanotheranostics

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In solid tumors, the limited diffusion of therapeutic molecules in the perivascular space is a known limitation impacting treatment efficacy. Ultrasound Targeted Microbubble Cavitation (UTMC) has been shown to increase vascular permeability and improve the delivery of therapeutic compounds including small molecules, antibodies (mAb), nanoparticles and even cells, notably across the blood-brain-barrier (BBB). In this study, we hypothesized that UTMC could improve the accumulation and biodistribution of mAb targeting the adenosinergic pathway (i.e. CD73) in mice bearing bilateral subcutaneous 4T1 mammary carcinoma. METHODS: A bolus of fluorescently labeled mAb was given intravenously, followed by a slow infusion of microbubbles. UTMC therapy (1 MHz, 850 kPa) was given under ultrasound image guidance for 5 minutes to the right side tumor only, using three different pulse lengths with identical ultrasound energy (5000cyc "long", 125x40cyc "mid" and 500x10cyc "short"), and leaving the left tumor as a paired control. Longitudinal accumulation at 0 h, 4 h and 24 h was measured using whole-body biofluorescence and confocal microscopy. RESULTS: Our data support an increase in antibody accumulation and extravasation (# extravasated vessels and extravasated signal intensity) at 0 h for all pulses and at 4 h for the mid and short pulses when compared to the control non treated side. However, this difference was not found at 24 h post UTMC, indicative of the transient nature of UTMC. Interestingly, confocal data supported that the highest extravasation range was obtained at 0 h with the long pulse and that the short pulse caused no increase in the extravasation range. Overall, the mid pulse was the only pulse to increase all our metrics (biofluorescence, fraction of extravasated vessels, amount of extravasated Ab, and extravasation range) at 0 h and 4 h time points. CONCLUSIONS: Our results support that UTMC can enhance antibody accumulation in solid tumors at the macroscopic and microscopic levels. This preferential accumulation was evident at early time points (0 h and 4 h) but had started to fade by 24 h, a time dependence that is consistent with the ultrasound blood brain barrier opening literature. Further development and optimization of this theranostic platform, such as repeated UTMC, could help improve antibody based therapies against solid cancer.

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“…However, despite growing interest and the availability of a wealth of weapons, biologicals included, no large-scale clinical investigation on the therapeutic efficacy of P2X7R blockade in cancer has been carried out, except a small study on skin tumors [37,65]. In this regard, the P2X7R, and in general P2 receptors, lags behind adenosine receptors which are now a major focus of attention in innovative cancer therapy [66]. Five A2A blockers are currently in clinical trials alone or in combination in cancer patients, with a good toxicity profile and encouraging preliminary results [66,67].…”

Section: Purinergic Signaling Sheds Light On the Biochemistry Of Thementioning

confidence: 99%

“…In this regard, the P2X7R, and in general P2 receptors, lags behind adenosine receptors which are now a major focus of attention in innovative cancer therapy [66]. Five A2A blockers are currently in clinical trials alone or in combination in cancer patients, with a good toxicity profile and encouraging preliminary results [66,67].…”

Section: Purinergic Signaling Sheds Light On the Biochemistry Of Thementioning

confidence: 99%

P2X7 is a cytotoxic receptor….maybe not: implications for cancer

Virgilio

2020

Purinergic Signalling

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The tumor microenvironment is rich in extracellular ATP. This nucleotide affects both cancer and infiltrating immune cell responses by acting at P2 receptors, chiefly P2X7. ATP is then degraded to generate adenosine, a very powerful immunosuppressant. The purinergic hypothesis put forward by Geoff Burnstock prompted innovative investigation in this field and provided the intellectual framework to interpret a myriad of experimental findings. This is a short appraisal of how Geoff’s inspiration influenced cancer studies and my own investigation highlighting the key role of the P2X7 receptor.

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The adenosine pathway in immuno-oncology

Cited by 358 publications

References 233 publications

Converging focal radiation and immunotherapy in a preclinical model of triple negative breast cancer: contribution of VISTA blockade

Converging focal radiation and immunotherapy in a preclinical model of triple negative breast cancer: contribution of VISTA blockade

The effect of ultrasound pulse length on microbubble cavitation induced antibody accumulation and distribution in a mouse model of breast cancer

P2X7 is a cytotoxic receptor….maybe not: implications for cancer

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