ESTRO 2021 Abstract Book
Results The enhancement of the abscopal effect compared to RT/αPD-1 was as follows: RT/αPD-1/Cis ( p < 0.01) > RT/αPD-1/Oxa ( p < 0.01) >> RT/αPD-1/Carbo ( p > 0.05) (B16 melanoma); RT/αPD-1/Cis ( p < 0.001) ≈ RT/αPD- 1/Carbo ( p < 0.01) >> RT/αPD-1/Oxa ( p > 0.05) (C51 model). Triple therapy with Cis resulted in complete abscopal regression in 7/15 and 8/9 mice bearing B16 or C51 tumors, respectively. Of note, triple therapy with Cis was also significantly better than the Cis/αPD-1 double combination in both tumor models (B16 model, p < 0.01; C51 model, p < 0.05). In vitro , the chemosensitivity was as follows: Cis ≈ Oxa > Carbo (B16 melanoma); Cis ≈ Carbo > Oxa (C51 colon carcinoma). Cis and Carbo induced more extracellular ATP than Oxa in both tumor cell lines. In the C51 model, triple therapy with Cis induced more mature dendritic cells ( p < 0.05), more Ki67+ CD8+ T cells ( p < 0.05), and more tumor-specific T cells ( p < 0.01) compared to triple therapy with Oxa. The enhanced abscopal effect was abrogated when CD8+ T cells were depleted or extracellular ATP signaling was blocked. Conclusion Both the chemosensitivity of tumor cells and the potency of chemotherapeutics to induce ATP secretion may be crucial for the platinum-mediated enhancement of the abscopal effect. Our findings may be important for the planning of clinical trials of triple combinations of RT, chemotherapy, and ICB in metastatic patients. OC-0185 Radiation plus PI3K-γδ inhibitor potentiated PD-1 blockade in murine and human breast cancer models I.A. Kim 1 , M.G. Han 2 , B.S. Jang 3 , M.H. Kang 3 1 Seoul National University, Radiation Oncology, Seoul , Korea Republic of; 2 Seoul National University , Tumor Biology, Seoul, Korea Republic of; 3 Seoul National University Bundang Hospital, Radiation Oncology, Seongnam, Korea Republic of Purpose or Objective The immune-suppressive tumor microenvironment (TME) of breast cancer responds poorly to immune checkpoint blockade (ICB) given alone. Radiation therapy (RT) possesses a potent immune stimulatory effect although it is known to promote immune suppression, increasing regulatory T cells (T reg ), myeloid- derived suppressor cells (MDSCs), and M2 tumor-associated macrophages (TAMs). We hypothesized that combined use of radiation therapy (RT) and a phosphoinositide 3-kinase (PI3K) γδ inhibitor to reduce immune suppression would enhance ICB efficacy. Materials and Methods Murine breast cancer cells (4T1) were grown in both immune-competent and -deficient BALB/c mice, and tumors were irradiated by 3 fractions of 24 Gy. A PD-1 blockade (10 mg/kg) and a PI3Kγδ inhibitor (IPI145; 15 mg/kg) were then administered every other day for 2 weeks. Fluorescence-activated cell sorting (FACS) and immunohistochemistry served to monitor subsequent changes in immune cell repertoire. We used mRNA- sequencing data of patient-derived breast cancer xenografts in a humanized NSG mouse model to analyze differentially expressed genes. Transcriptomic and clinical data were acquired from The Cancer Genome Atlas (TCGA) pan-cancer cohort, and a deconvolution algorithm (xCell) was used to profile immune cellular distributions at certain levels (high vs. low) of PI3Kγδ expression. Results In the immune-competent syngenic 4T1 murine tumor model, PD-1 blockade alone led to tumor hyperprogression, whereas a three-pronged strategy of PI3Kγδ inhibitor, RT, and PD-1 blockade significantly delayed primary tumor growth, boosted abscopal effect, and improved animal survival by comparison. The immune-deficient syngeneic 4T1 murine tumor model failed to show this synergism in delaying tumor growth. According to FACS analysis, RT significantly increased not only CD8 + cytotoxic T-cell fractions but also immune- suppressive T reg cells, MDSCs, and M2 TAMs. However, PI3Kγδ inhibitor significantly lowered proportions of T reg , MDSCs, and M2 TAMs, achieving dramatic gains in splenic, nodal, and tumor CD8 + T-cell populations after triple combination therapy. There were significantly decreased tumor expression of p-AKT, PD-L1, and HIF1αby PI3Kγδ inhibition. Triple combination therapy significantly delayed primary tumor growth in a humanized PDX model. The analyses of RNAseq data of humanized PDX showed triple combination increased immune response pathways and increased CD8 T cell and decreased Treg and M2 macrophage shown by the Xcell deconvolution. In the TCGA pan-cancer cohort, higher tumor purity-adjusted T reg /CD8 + T-cell and M2/M1 TAM ratios and worse overall patient survival were associated with high PIK3CG (PI3Kγ) or PIK3CD (PI3Kδ)
These findings collectively indicate that PI3Kγand PI3Kδare clinically relevant targets in an immunosuppressive TME. Combining PI3Kγδinhibitor, RT, and PD-1 blockade may thus be a viable approach, helping to overcome the therapeutic resistance of immunologically cold tumors such as breast cancer.
OC-0186 Innate immune signalling and immunogenic cell death upon treatment with radiation and ATR inhibitors A. Eek Mariampillai 1 , S. Hauge 1 , R.G. Syljuåsen 1 1 Institute for Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Department of Radiation Biology, Oslo, Norway Purpose or Objective Inhibitors of the cell cycle checkpoint kinase ATR are considered promising as radiosensitisers. ATR inhibition leads to abrogation of the radiation-induced G 2 /M cell cycle checkpoint and suppression of DNA damage repair, causing mitotic catastrophe and subsequent cell death. Interestingly, recent studies suggest that ATR inhibition may also increase radiation-induced antitumour immune responses. However, the underlying immunomodulatory mechanisms and the impact of these in human cancers remain poorly understood. We aimed to assess whether ATR inhibition can potentiate radiation-induced type I interferon (IFN) signalling and
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