CD73 Expression Is an Independent Prognostic Factor in Prostate Cancer

Abstract

Purpose: CD73 is an adenosine-generating ecto-enzyme that suppresses antitumor immunity in mouse models of cancer, including prostate cancer. Although high levels of CD73 are associated with poor prognosis in various types of cancer, the clinical impact of CD73 in prostate cancer remains unclear.Experimental Design: We evaluated the prognostic value of CD73 protein expression and CD8 þ cell density in 285 cases of prostate cancer on tissue microarray (TMA). Normal adjacent and tumor tissues were evaluated in duplicates.Results: Univariate and multivariate analyses revealed that high levels of CD73 in normal adjacent prostate epithelium were significantly associated with shorter biochemical recurrence (BCR)-free survival. Notably, CD73 expression in normal epithelium conferred a negative prognostic value to prostate-infiltrating CD8 þ cells. Surprisingly, high levels of CD73 in the tumor stroma were associated with longer BCR-free survival in univariate analysis. In vitro studies revealed that adenosine signaling inhibited NF-kB activity in human prostate cancer cells via A2B adenosine receptors. Consistent with these results, CD73 expression in the prostate tumor stroma negatively correlated with p65 expression in the nuclei of prostate tumor cells. Conclusions: Our study revealed that CD73 is an independent prognostic factor in prostate cancer. Our data support a model in which CD73 expression in the prostate epithelium suppresses immunosurveillance by CD8 þ T cells, whereas CD73 expression in the tumor stroma reduces NF-kB signaling in tumor cells via A2B adenosine receptor signaling. CD73 expression, including in normal adjacent prostate epithelium, can thus effectively discriminate between aggressive and indolent forms of prostate cancer.

Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis

“…High ADORA2B expression is associated with worse patient outcome CD73-adenosine signaling pathway has been implicated in promoting tumor growth and metastases (1,2,(25)(26)(27). We have previously shown that high CD73 expression is associated with a poor prognosis in the primary TNBC subtype, and its overexpression in these tumors predicted chemoresistance to doxorubicin therapy (26).…”

Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy

“…Although the association between CD73/CD39 expression and patient prognosis is complex (39), in many cases the expression of CD73 has been shown to negatively correlate with patient survival. This includes patient cohorts in breast (20), ovarian (22), renal cell (40), rectal adenocarcinoma (41), and prostate cancer (42). Furthermore, targeting this pathway has been shown to enhance clinical responses to chemotherapy (20) and other classes of immunotherapy (33,43,44).…”

“…CD73 is expressed on both tumor cells and host immunosuppressive cells such as Tregs and myeloid-derived suppressor cells (MDSCs). CD73 expression has been shown to negatively correlate with patient prognosis in a number of cancer types (20)(21)(22), highlighting the relevance of the CD73/adenosine immunosuppressive axis in patients. Furthermore, preclinical studies have shown that targeting of either CD73…”

Role of adenosine in tumor progression: focus on A2B receptor as potential therapeutic target

“…[42][43][44][45][46] CD73-deficient mice are resistant to tumor and show an increased influx of CD8 + T cells [44] and low number of Tregs within the tumor. [47] The expression of CD73 on various tumor cells from cancer patients, including breast, [46] glioblastoma, [48] prostate, [49] ovarian, [50] leukemia [51] has been associated with poor prognosis. Notably, some chemotherapeutics are able to increase the expression of CD73 on cancer cells, which may in turn represent a putative mechanism of resistance to chemotherapeutics.…”

“…Notably, some chemotherapeutics are able to increase the expression of CD73 on cancer cells, which may in turn represent a putative mechanism of resistance to chemotherapeutics. [46,49,51] On the other hand, targeting CD73 can improve the therapeutic potential of some conventional cancer treatments, including chemotherapy, radiotherapy and immunotherapy. For example, inhibition of CD73 in combination with doxorubicin prolonged the survival of mice with metastatic breast cancer.…”