Co-inhibition of CD73 and A2AR Adenosine Signaling Improves Anti-tumor Immune Responses

Young, Arabella; Ngiow, Shin Foong; Barkauskas, Deborah S.; Sult, Erin; Hay, Carl; Blake, Stephen J.; Huang, Qihui; Liu, Jing; Takeda, Kazuyoshi; Teng, Michele W.L.; Sachsenmeier, Kris F.; Smyth, Mark J.

doi:10.1016/j.ccell.2016.06.025

Cited by 323 publications

(327 citation statements)

References 56 publications

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“…13,14 MEDI9447 was developed to minimize Fc-receptor (FcR) engagement; however, a recent study by Young et al identified that the anti-metastatic activities of anti-CD73 mAb were largely reliant on the ability of the mAb to engage Fc receptor, in particular, FcgRIV on CD11b C Gr-1 C myeloid cells. 11 Similar studies in the past have been instrumental in deciphering the mechanism underlying the clinical activities of anti-CTLA-4, 15,16 and anti-HER2 17 mAbs. In the current study, we assessed more extensively whether the control of primary tumors and their metastases by anti-CD73 mAbs always required the activation of Fc-receptors.…”

Section: Introductionmentioning

confidence: 86%

“…Previously, we demonstrated that anti-CD73 mAb, TY/23, was able to control B16F10-CD73 hi experimental metastasis, and this required CD73 expression on tumors as well as FcgRIV engagement. 11 Work by Simpson et al had also demonstrated that different antibody isotypes can differentially bind FcR and that this influences the nature of antitumor response. 19 Given that three of our antibody clones were triple mutated in the Fc region; we investigated how treatment with these clones would impact on metastasis burden (Fig.…”

Section: Only Fcr Engaging Anti-cd73 Mabs Significantly Suppress Tumomentioning

confidence: 99%

“…These observations were also in concert with our previously published results. 11 Given this strong anti-metastatic effect by 2C5 (mIgG2a), we next investigated which Fc-receptor cross-links with 2C5 (mIgG2a) to mediate this effect. Treatment of WT mice with 2C5 (mIgG2a) suppressed the number of B16F10-CD73 hi lung metastases.…”

Section: Only Fcr Engaging Anti-cd73 Mabs Significantly Suppress Tumomentioning

confidence: 99%

“…Indeed, anti-CD73 mAb treatment is effective in inhibiting the growth of primary tumors and their metastases in mice. 9,10,11 Anti-CD73 monotherapy has clinical promise, but studies also indicated that these mAbs effectively synergized with anti-PD-1 or anti-CTLA-4 mAbs. 12 Additionally, our recent findings identified that co-targeting molecules within the adenosinergic pathway displayed a synergistic reduction in the number of lung metastases.…”

Section: Introductionmentioning

confidence: 99%

“…12 Additionally, our recent findings identified that co-targeting molecules within the adenosinergic pathway displayed a synergistic reduction in the number of lung metastases. Specifically, the combination blockade of CD73 and A2AR provided improved therapeutic efficacy over monotherapy alone, 11 thus reflecting the non-redundant nature of these molecules in mediating antitumor immunity.…”

Section: Introductionmentioning

confidence: 99%

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Selective activation of anti-CD73 mechanisms in control of primary tumors and metastases

et al. 2017

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The emerging role for CD73 in driving cancer growth and metastasis has presented opportunities to develop anti-CD73 monoclonal antibodies (mAbs) in the treatment of human cancers. Blockade of CD73 by antagonistic CD73 mAbs ameliorates tumor growth and metastasis via the inhibition of enzymatic and non-enzymatic CD73 pathways. In this study, we investigated whether Fc-receptor cross-linking represented a non-redundant mechanism by which anti-CD73 mAbs exert potent suppression of solid tumors and metastases. We engineered four anti-CD73 mAbs, each different in their ability to modulate CD73 enzymatic function and bind Fc receptors. mAbs recognizing a similar epitope of CD73 (CD73-04, TY/23 and 2C5) displayed the greatest antitumor activity. Importantly, we observed that the optimal control of metastasis by anti-CD73 mAbs involved primarily Fc receptor engagement, while suppression of solid tumors required both, enzyme inhibition and activation of Fc receptors. Engagement of Fc-receptors was also essential for optimal anti-metastatic effect in combination with either A2AR inhibitor or anti-PD-1 mAb treatment. The control of experimental metastases relied on the activation of host NK cells and IFNg, while NK cells, CD8 C T cells and IFNg were needed for effective antitumor effect in the spontaneous metastases model. These observations advance our understanding of the enzymatic and non-enzymatic functions of anti-CD73 mAbs in solid tumors and metastases. Altogether, these findings will greatly assist in the design of anti-CD73 mAbs to be used as either single agents or in combination with other immunotherapeutic molecules or targeted therapies.

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Section: Introductionmentioning

confidence: 86%

Section: Only Fcr Engaging Anti-cd73 Mabs Significantly Suppress Tumomentioning

confidence: 99%

Section: Only Fcr Engaging Anti-cd73 Mabs Significantly Suppress Tumomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Selective activation of anti-CD73 mechanisms in control of primary tumors and metastases

et al. 2017

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Immunosuppressive enzymes in the tumor microenvironment

Molinier‐Frenkel

Castellano

2017

FEBS Letters

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Antigen encounter by T lymphocytes induces important metabolic changes. Antitumor T lymphocytes enter in a metabolic competition with tumors, which divert feedback mechanisms of the immune response. Immunosuppressive enzymes, modifying the nutrient availability and leading to the production of toxic catabolites, represent one of these mechanisms, contributing to the metabolic halo in which T lymphocytes evolve during immune responses. Two classes of immunosuppressive enzymes, expressed by the tumor cells or by cells of the microenvironment, have been described: those catabolizing essential or semiessential amino acids, tryptophan, arginine, and phenylalanine and the ectoenzymes, which degrade the ATP to produce adenosine. These enzymes are described, as well as some of the ongoing clinical trials aiming to block them in cancer treatment.

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Sustained compensatory p38 MAPK signaling following treatment with MAPK inhibitors induces the immunosuppressive protein CD73 in cancer: combined targeting could improve outcomes

et al. 2021

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RAS-MAPK signaling promotes immune evasion and cancer cell survival, and MAPK inhibitors (MAPKi) are frequently used as cancer therapies. Despite progress elucidating the direct effects of MAPKi on immune cells, their indirect effect on the tumor microenvironment (TME) through changes in tumor cells remains incompletely understood. Here, we present evidence of a rapid compensatory response to MAPKi that is driven by sustained p38-MAPK signaling and by which cancer cells can upregulate the immunosuppressive protein CD73 to reduce the anti-tumor immune response. This compensatory response also results in decreased sensitivity towards MAPKi and, accordingly, combining anti-CD73 antibodies and MAPKi significantly enhances the anti-tumor effect compared to single-agent treatment in vivo. Combining MAPKi and anti-CD73 was accompanied by significant alterations in intratumor immune-cell composition, supporting the effect of MAPKi-induced CD73 expression on the TME. We show that high CD73 expression significantly correlates with worse outcome in MAPKi-treated colorectal cancer patients, highlighting the potential clinical importance of increased CD73 expression following MAPKi treatment. Our findings may explain the diminished effect of MAPKi in cancer patients and provides further rationale for combined anti-CD73 and MAPKi treatment.

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Co-inhibition of CD73 and A2AR Adenosine Signaling Improves Anti-tumor Immune Responses

Cited by 323 publications

References 56 publications

Selective activation of anti-CD73 mechanisms in control of primary tumors and metastases

Selective activation of anti-CD73 mechanisms in control of primary tumors and metastases

Immunosuppressive enzymes in the tumor microenvironment

Sustained compensatory p38 MAPK signaling following treatment with MAPK inhibitors induces the immunosuppressive protein CD73 in cancer: combined targeting could improve outcomes

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