CD73 blockade enhances the local and abscopal effects of radiotherapy in a murine rectal cancer model

Abstract

Background: Anti-tumor effects of radiation therapy (RT) largely depend on host immune function. Adenosine with its strong immunosuppressive properties is an important immune checkpoint molecule. Method: We examined how intra-tumoral adenosine levels modify anti-tumor effects of RT in a murine model using an anti-CD73 antibody which blocks the rate-limiting enzyme to produce extracellular adenosine. We also evaluated CD73 expression in irradiated human rectal cancer tissue. Results: LuM-1, a highly metastatic murine colon cancer, expresses CD73 with significantly enhanced expression after RT. Subcutaneous (sc) transfer of LuM-1 in Balb/c mice developed macroscopic sc tumors and microscopic pulmonary metastases within 2 weeks. Adenosine levels in the sc tumor were increased after RT. Selective RT (4Gyx3) suppressed the growth of the irradiated sc tumor, but did not affect the growth of lung metastases which were shielded from RT. Intraperitoneal administration of anti-CD73 antibody (200 μg × 6) alone did not produce antitumor effects. However, when combined with RT in the same protocol, anti-CD73 antibody further delayed the growth of sc tumors and suppressed the development of lung metastases presumably through abscopal effects. Splenocytes derived from RT+ CD73 antibody treated mice showed enhanced IFN-γ production and cytotoxicity against LuM-1 compared to controls. Immunohistochemical studies of irradiated human rectal cancer showed that high expression of CD73 in remnant tumor cells and/or stroma is significantly associated with worse outcome. Conclusion: These results suggest that adenosine plays an important role in the anti-tumor effects mediated by RT and that CD73/adenosine axis blockade may enhance the anti-tumor effect of RT, and improve the outcomes of patients with locally advanced rectal cancer.

Photon versus carbon ion irradiation: immunomodulatory effects exerted on murine tumor cell lines

“…8 Gy [9][10][11][12][13] , as well as ablative single doses up to 60 Gy 11,[14][15][16] , to be most effective in inducing inflammatory stimuli and concomitant immune responses, particularly when combined with antibody administration against PD-L1 and/or CTLA-4 17 .…”

Metformin Combined with Local Irradiation Provokes Abscopal Effects in a Murine Rectal Cancer Model

“…No metastases were detected in 3/10 mice. Since microscopic metastases from the primary LuM-1 tumor were already present in the lungs at the time of starting treatment 49 , this indicates that metformin not only enhances the cytotoxic effects on tumor cells directly exposed to RT but also causes tumor regression outside the irradiated eld as a so-called "abscopal effect" 30,50 .…”

“…When the primary tumors reached a volume of 100 to 300 mm 3 at day13, mice were divided into four groups, each group containing 5~6 mice to enable statistical analysis (Group A, no treatment; Group B, metformin treated; Group C, radiation treated; Group D, metformin and radiation treated). Local RT was delivered using MX 160 Labo (mediXtec, Chiba, Japan), as described previously 49 . In short, anesthetized mice were held in the decubitus position, and radiation delivered only to the subcutaneous (sc) tumor with the remainder of the mouse including the lung covered with a 5 mm lead plate.…”

Abscopal Effect and Drug-Induced Xenogenization: A Strategic Alliance in Cancer Treatment?

“…Indeed, blockade of CD73 has been shown to enhance radiation-associated tumor infiltration by DC in the absence of type 1 IFN induction while improving systemic antitumor T-cell responses [ 94 ]. In the LuM-1 preclinical model, a highly metastatic murine colon cancer, expression of CD73 was significantly increased after RT [ 99 ]. In subcutaneous lesions of the same tumor model and microscopic pulmonary metastases occurring in Balb/c mice, characterized by increased levels of adenosine after RT, intraperitoneal anti-CD73 antibody alone did not produce antitumor effects.…”