Faculty Bibliography

Radiotherapy is under investigation for its ability to enhance responses to immunotherapy. However, the mechanisms by which radiation induces anti-tumour T cells remain unclear. We show that the DNA exonuclease Trex1 is induced by radiation doses above 12-18 Gy in different cancer cells, and attenuates their immunogenicity by degrading DNA that accumulates in the cytosol upon radiation. Cytosolic DNA stimulates secretion of interferon-beta by cancer cells following activation of the DNA sensor cGAS and its downstream effector STING. Repeated irradiation at doses that do not induce Trex1 amplifies interferon-beta production, resulting in recruitment and activation of Batf3-dependent dendritic cells. This effect is essential for priming of CD8+ T cells that mediate systemic tumour rejection (abscopal effect) in the context of immune checkpoint blockade. Thus, Trex1 is an upstream regulator of radiation-driven anti-tumour immunity. Trex1 induction may guide the selection of radiation dose and fractionation in patients treated with immunotherapy.

BACKGROUND:mutations are highly penetrant in causing various types of spontaneous tumors that often exhibit resistance to anticancer therapies including immunotherapy. Recent studies demonstrate that PTEN also regulates immune functionality. OBJECTIVE:To understand the multifaceted functions of PTEN as both a tumor suppressor and an immune regulator. METHODS:This review will summarize the emerging knowledge of PTEN function in cancer immunoediting. In addition, the mechanisms underlying functional integration of various PTEN pathways in regulating cancer evolution and tumor immunity will be highlighted. RESULTS:Recent preclinical and clinical studies revealed the essential role of PTEN in maintaining immune homeostasis, which significantly expands the repertoire of PTEN functions. Mechanistically, aberrant PTEN signaling alters the interplay between the immune system and tumors, leading to immunosuppression and tumor escape. CONCLUSION/CONCLUSIONS:Rational design of personalized anti-cancer treatment requires mechanistic understanding of diverse PTEN signaling pathways in modulation of the crosstalk between tumor and immune cells.

Radiation therapy (RT) induces release of ATP in the tumor micro environment (TME) triggering recruitment and activation of dendritic cells (DCs), including CD103 DCs, identi+ed as the key DC subsetresponsible for cross-presentation of tumor antigens to CD8 T cells. However, CD39 and CD73-expressing cells in the TME hydrolyze ATP into adenosine that potently inhibits DCs and CD8 T cells. Here, we tested the hypothesis that adenosine generation limits the ability of RT totrigger anti-tumor immunity. Wild type (WT) or BATF3 mice (CD103 DC-de+cient) were inoculated s.c. with TSA tumor cells (day 0) and assigned to treatment with: (1) control Ab; (2) anti-CD73 Ab (100 mug) (3) RT (20 Gy); (4) RT + anti-CD73 Ab. Antibodies were administered i.p. on day 11, 14, 17 and 20. RT was given locally as single 20 Gy dose on day 12. On day 18, tumors were analyzed by -ow cytometry for DC and T cell in+ltration. Mice were monitored for tumor progression. DCs generated in vitro by culture of bone marrow from WT mice with Flt3L (>90% CD103 ) were labeled with CFSE and intravenously injected in BATF3 recipient mice. Tumors were harvested after 48h and analyzed by -ow cytometry for in+ltration of CFSE+ DCs. In tumors of RT- but not sham-treated mice, anti-CD73 mAb increased in+ltration of CD103 DCs and enhanced CD8 T cell/Treg ratio. Importantly, CD73 blockade had no anti-tumor e

EMBASE:617353266

ISSN: 1550-6606

CID: 2645572