ESTRO 2021 Abstract Book
depletion did not affect that in SIRT2-overexpressing mice. Lastly, pharmacological inhibition of SIRT2 increased NK cell tumor infiltration and suppressed melanoma tumor growth. Conclusion Systemic SIRT2 and NK cell activity exhibit a dynamic functional interaction which promotes melanoma tumor progression. Given the recent renewed interest in NK-cell-mediated immunotherapy response, SIRT2 could represent a new opportunity to mediate immunotherapy response and resistance. OC-0183 Hypofractionated radiation synergizes with lenalidomide to induce an abscopal immune response K. Onyshchenko 1,2,3,4 , R. Luo 1,2,3,4 , G. Niedermann 1,3,4 1 Faculty of Medicine, University of Freiburg, Department of Radiation Oncology, Freiburg im Breisgau, Germany; 2 University of Freiburg, Faculty of Biology, Freiburg im Breisgau, Germany; 3 Partner Site Freiburg, German Cancer Consortium (DKTK), Freiburg im Breisgau, Germany; 4 German Cancer Research Center, DKFZ, Heidelberg, Germany Purpose or Objective Localized hypofractionated radiotherapy (hRT) can promote the cross-presentation of tumor antigens to CD8+ T cells, but distant T cell-mediated effects can usually only be observed in conjunction with immune checkpoint blockade (ICB). Moreover, in patients, the RT-induced abscopal effect is still only rarely observed and many patients experience ICB-induced adverse events. Lenalidomide (lena) is an anti-angiogenic and immunomodulatory drug used in the treatment of multiple myeloma. We here investigated whether lena can enhance the RT-induced abscopal effect in double combination with hRT. Materials and Methods We used abscopal tumor models with one irradiated and one non-irradiated tumor in opposite flanks. In the B16 melanoma model, hRT was delivered to the primary tumor in two fractions of 12 Gy; in the MC38 colon carcinoma model, it was delivered in three fractions of 8 Gy. Tumor growth and survival were determined (7– 12 mice per group). Lena (1 mg/mouse) was injected i.p. daily for 3 weeks. Tumor-specific CD8+ T cells were measured by FACS using MHC tetramers in single-cell suspensions of tumors and lymph nodes. Dependence on CD8+ T cells and type-I interferon (IFN) was determined by antibody blockade. Secretion of type-I IFNs was measured using B16-blue IFN-α/β reporter cells in vitro . Cross-presentation of tumor antigen by dendritic cells (DCs) was measured using the B16-OVA model and an antibody recognizing MHC/OVA-epitope complexes ex vivo . Results In both tumor models, double combination of hRT with lena induced a pronounced abscopal effect. The control of the non-irradiated tumor was much better than after monotherapy with hRT or lena (B16 model: p < 0.005; MC38 model: p < 0.05). Survival of the mice was also significantly improved compared to single treatment with hRT (B16: p < 0.001, MC38: p < 0.05) or lena (B16: p < 0.001, MC38: p < 0.0001). The abscopal effect was strongly dependent on CD8+ T cells and correlated with an increase in tumor-specific CD8+ T cells in the non-irradiated tumor and its draining lymph nodes. Additionally, we observed an increase in tumor- specific T cells with a stem-like (PD1+ TCF1+ TIM3–) and a transitory exhausted phenotype (PD1+ TIM3+ CD101– ) as well as an increase in T cells expressing effector molecules such as GzmB, IFNg, and TNF. Lena also increased type-I IFN production in tumor cells. Moreover, hRT/lena combination treatment increased the number of DCs cross-presenting OVA to CD8+ T cells, compared to hRT alone. In addition, blocking the type-I IFN receptor, known to be essential for cross-presentation, completely abrogated the abscopal effect induced by lena. Conclusion We found that lena can cooperate with hRT to induce an abscopal effect, which was similar to the effect seen with hRT + anti-PD-1 in the two models. Mechanistically, lena cooperated with hRT to enhance the cross- priming of tumor antigen to CD8+ T cells, at least in part by increasing the production of type-I IFN. OC-0184 Comparison of the potency of clinically relevant platinum derivatives to enhance the abscopal effect R. Luo 1,2,3,4 , K. Onyshchenko 1,2,3,4 , L. Wang 1 , E. Firat 1 , G. Niedermann 1,3,5 1 Faculty of Medicine, University of Freiburg, Department of Radiation Oncology, Freiburg im Breisgau, Germany; 2 University of Freiburg, Faculty of Biology, Freiburg im Breisgau, Germany; 3 Partner Site Freiburg, German Cancer Consortium (DKTK), Freiburg im Breisgau, Germany; 4 German Cancer Research Center, DKFZ, Heidelberg, Germany; 5 German Cancer Research Center, DKFZ, Freiburg im Breisgau, Germany Purpose or Objective Localized radiotherapy (RT) can cause T cell-mediated abscopal effects on non-irradiated metastases, particularly in combination with immune checkpoint blockade (ICB). However, results of prospective clinical trials have not met the expectations. We study whether chemotherapeutics can enhance the abscopal effect. Oxaliplatin (Oxa) has been considered as immunogenic, but cisplatin (Cis) and carboplatin (Carbo) have not. We compared these three platinum derivatives in two different abscopal mouse models. Materials and Methods In mice bearing bilateral tumors, the primary tumor was irradiated with 2 × 12 Gy (B16 melanoma model) or 2 × 8 Gy (C51 colon carcinoma model); Cis, Carbo, or Oxa were given once together with RT; anti-PD1 was given weekly. Tumor growth and survival of mice were determined (5–15 mice per group). The dependence of the therapeutic effects on CD8+ T cells and on extracellular ATP was determined by using T cell-depleting antibodies and PPADS (a nontoxic broad-spectrum inhibitor of purinergic receptors), respectively. Frequencies and functionality (differentiation and exhaustion state) of tumor-specific CD8+ T cells were determined by FACS using MHC tetramers and various antibodies. In vitro , we determined the chemosensitivity of the tumor cell lines and their production of extracellular ATP using CellTiter-Glo ® 2.0.
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