Cd73: An Emerging Checkpoint for Cancer Immunotherapy

Abstract

CD73 is a novel immune checkpoint associated with adenosine metabolism that promotes tumor progression by suppressing antitumor immune response and promoting angiogenesis. The inhibition of CD73, in combination with immune checkpoint blockade, targeted therapy or conventional therapy, improves antitumor effects in numerous preclinical mouse models of cancer. Emerging evidence suggests that the combination of anti-CD73 and immune checkpoint blockade has promising clinical activity in patients with advanced solid tumors. In this review, we will discuss the specific role of CD73 on both tumor cells and nontumor cells in regulating tumor immunity and tumorigenesis and provide an update on the current view of the antitumor activity of targeting CD73 by mAb or small molecule selective inhibitors in preclinical and clinical settings.

The expression of the adenosine pathway markers CD39 and CD73 in salivary gland carcinomas harbors the potential for novel immune checkpoint inhibition

“…In keeping with results from lung adenocarcinoma (LUAD) and other solid tumors, we found implications for higher T cell infiltration in tumors with high CD73 expression levels on immune cells suggesting a rationale for the combination of therapeutic CD73 inhibition and ICI (Roh et al 2020 ; Rocha et al 2021 ; Reinhardt et al 2017 ; Goswami et al 2020 ). In contrast to our results, a frequent CD73 was found on tumor cells across a variety of solid tumors (Chen et al 2019 ; Ma et al 2019 ). However, several entities among the spectrum of aggressive solid tumors were associated with low CD73 expression levels (Eroglu et al 2000 ; Durak et al 1993 ; Rackley et al 1989 ).…”

The expression of the adenosine pathway markers CD39 and CD73 in salivary gland carcinomas harbors the potential for novel immune checkpoint inhibition

“…In keeping with results from lung adenocarcinoma (LUAD) and other solid tumors, we found implications for higher T cell infiltration in tumors with high CD73 expression levels on immune cells suggesting a rationale for the combination of therapeutic CD73 inhibition and ICI (Roh et al 2020 ; Rocha et al 2021 ; Reinhardt et al 2017 ; Goswami et al 2020 ). In contrast to our results, a frequent CD73 was found on tumor cells across a variety of solid tumors (Chen et al 2019 ; Ma et al 2019 ). However, several entities among the spectrum of aggressive solid tumors were associated with low CD73 expression levels (Eroglu et al 2000 ; Durak et al 1993 ; Rackley et al 1989 ).…”

SpheroMap Cytometry: a novel spatial flow cytometry approach to evaluate immune response in PDAC spheroids

“…More specifically, myCAFs have been shown to exert a suppressive effect on CD8 + T cells 19, 21-23 . As confirmed in the study conducted by our research group, CD73 is highly expressed in PDAC tumors, particularly in stromal cells 24-27 ; previous work has shown that CD73 overexpression is associated with reduced infiltration of CD8 + tumor-infiltrating lymphocytes and with Treg-mediated immunosuppression, since this mechanism depends on extracellular adenosine generated by CD73 28, 29 . In this context, our findings align with published data on the impact of the stromal component and hypoxia on immune-cell infiltration 30-34 .…”

Medicinal Chemistry Strategies for the Development of CD73 Inhibitors in Cancer Immunotherapy

“…The structural data revealed critical steric and electronic constraints governing ligand accommodation, correlating with the observed potency trends where small substituents (23) outperformed bulkier analogs (25).…”

The expression of the adenosine pathway markers CD39 and CD73 in salivary gland carcinomas harbors the potential for novel immune checkpoint inhibition

“…In keeping with results from lung adenocarcinoma (LUAD) and other solid tumors, we found implications for higher T cell infiltration in tumors with high CD73 expression levels on immune cells suggesting a rationale for the combination of therapeutic CD73 inhibition and ICI (Roh et al 2020 ; Rocha et al 2021 ; Reinhardt et al 2017 ; Goswami et al 2020 ). In contrast to our results, a frequent CD73 was found on tumor cells across a variety of solid tumors (Chen et al 2019 ; Ma et al 2019 ). However, several entities among the spectrum of aggressive solid tumors were associated with low CD73 expression levels (Eroglu et al 2000 ; Durak et al 1993 ; Rackley et al 1989 ).…”

SpheroMap Cytometry: a novel spatial flow cytometry approach to evaluate immune response in PDAC spheroids

“…More specifically, myCAFs have been shown to exert a suppressive effect on CD8 + T cells 19, 21-23 . As confirmed in the study conducted by our research group, CD73 is highly expressed in PDAC tumors, particularly in stromal cells 24-27 ; previous work has shown that CD73 overexpression is associated with reduced infiltration of CD8 + tumor-infiltrating lymphocytes and with Treg-mediated immunosuppression, since this mechanism depends on extracellular adenosine generated by CD73 28, 29 . In this context, our findings align with published data on the impact of the stromal component and hypoxia on immune-cell infiltration 30-34 .…”

Medicinal Chemistry Strategies for the Development of CD73 Inhibitors in Cancer Immunotherapy

“…The structural data revealed critical steric and electronic constraints governing ligand accommodation, correlating with the observed potency trends where small substituents (23) outperformed bulkier analogs (25).…”

The expression of the adenosine pathway markers CD39 and CD73 in salivary gland carcinomas harbors the potential for novel immune checkpoint inhibition

“…In keeping with results from lung adenocarcinoma (LUAD) and other solid tumors, we found implications for higher T cell infiltration in tumors with high CD73 expression levels on immune cells suggesting a rationale for the combination of therapeutic CD73 inhibition and ICI (Roh et al 2020 ; Rocha et al 2021 ; Reinhardt et al 2017 ; Goswami et al 2020 ). In contrast to our results, a frequent CD73 was found on tumor cells across a variety of solid tumors (Chen et al 2019 ; Ma et al 2019 ). However, several entities among the spectrum of aggressive solid tumors were associated with low CD73 expression levels (Eroglu et al 2000 ; Durak et al 1993 ; Rackley et al 1989 ).…”

SpheroMap Cytometry: a novel spatial flow cytometry approach to evaluate immune response in PDAC spheroids

“…More specifically, myCAFs have been shown to exert a suppressive effect on CD8 + T cells 19, 21-23 . As confirmed in the study conducted by our research group, CD73 is highly expressed in PDAC tumors, particularly in stromal cells 24-27 ; previous work has shown that CD73 overexpression is associated with reduced infiltration of CD8 + tumor-infiltrating lymphocytes and with Treg-mediated immunosuppression, since this mechanism depends on extracellular adenosine generated by CD73 28, 29 . In this context, our findings align with published data on the impact of the stromal component and hypoxia on immune-cell infiltration 30-34 .…”

Medicinal Chemistry Strategies for the Development of CD73 Inhibitors in Cancer Immunotherapy

“…The structural data revealed critical steric and electronic constraints governing ligand accommodation, correlating with the observed potency trends where small substituents (23) outperformed bulkier analogs (25).…”