Uniform Topological Spaces Based on BF-ideals in Negative Non-involutive Residuated Lattices

Uniform Topological Spaces Based on BF-ideals in Negative Non-involutive Residuated Lattices

Mini Oral Sessions S125 Volume 105  Number 1S  Supplement 2019 CD45+ leukocytes. Transcriptomics were performed on sorted CD45+ leukocytes from PhR...

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Mini Oral Sessions S125

Volume 105  Number 1S  Supplement 2019 CD45+ leukocytes. Transcriptomics were performed on sorted CD45+ leukocytes from PhRT-treated tumors by RNAseq. Results: PhRT induced a significant dose-dependent shift towards an immunosuppressive phenotype within the myeloid compartment. Following very low (0.75 Gy), low (2 Gy) and high-dose (8 Gy) PhRT there was 40%, 54%, and 60% (p<0.001) reduction in the pro-inflammatory, anti-tumor M1-like macrophages (CD45+CD11b+MHCII+Ly6C-), compared to control. This dose-dependent decrease in the M1-like population was accompanied by a 57%, 77% and 91% (p<0.001) increase in the immunosuppressive M2-like macrophages (CD45+CD11b+MHCIILy6C-) following very low (0.75 Gy), low (2 Gy) and high-dose (8 Gy) PhRT, respectively. Notably, low (2 Gy) and high-dose (8 Gy) PhRT increased the abundance of monocytic myeloid-derived suppressor cells (Ly6C+Ly6G-F480-CD11b+; M-MDSCs) by 105% and 245% (p<0.001), respectively, with no significant change by very low dose (0.75 Gy) PhRT. Only high dose (8 Gy) PhRT increased the abundance of the potent immunosuppressive Arg1+ M2 cells, inducing a 130% increase (p<0.001) compared to control. High dose (8 Gy) PhRT also resulted in a 51% (p<0.05) increase in tissue-resident, cross-presenting dendritic cells (CD45+CD103+CD11b-Ly6C-MHCII-hi), compared to control. Transcriptome analysis of CD45+ leukocytes revealed a significant dosedependent upregulation of the type I-interferon signaling pathway. Whereas, very low dose (0.75 Gy) PhRT down-regulated TGF-b signaling. Conclusion: PhRT behaves as a potent immunomodulator, inducing immunophenotypic changes within the tumor microenvironment at doses as low as 0.75 Gy. Here, we demonstrate a dose-dependent increase in immunosuppressive myeloid cells and type I interferon signaling. These data suggest that at early time points, higher doses of PhRT may create a more immunosuppressive microenvironment that may interfere with recruitment and influx of cytotoxic lymphocytes, thus blunting an antitumor immune response. Author Disclosure: C.S. Spina: Employee; Concerto Health AI. Stock; Concerto Health AI. Z.A. Lopez Bujanda: Patent/License Fees/Copyright; cMethDNA technology: U.S. Pat. No. 8,062,849. W. Mao: None. M. Chaimowitz: None. C. Zhang: None. N. Chowdhury: None. D.H. Aggen: Consultant; Boehringer Ingelheim. Royalty; University of Illinois. H. Li: Employee; Mayo Clinic. C.G. Drake: Research Grant; BristolMyers Squibb, Aduro Biotech, Janssen Oncology, Compugen. Consultant; AstraZeneca/MedImmune, Britton-Myers Squibb, Compugen, Dendreon, Janssen Oncology, Pfizer, Astellas Medivation, Tizona Therapeutics, Potenza Therapeutics, Agenus, NexImmune, Merck, ImmuneXcite, Pierre Fabre, Lilly. Stock; Compugen, ImmuneXcite, Pote.

1022 High Peripheral Regulatory T Cells Independently Predict Poor Outcomes for Stereotactic Ablative Radiotherapy of Pulmonary Recurrence-Based Oligometastatic Non-Small Cell Lung Cancer C. Liu,1,2 B. Sun,3 X. Hu,2 J. Yue,2 and J. Yu1,2; 1Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China, 2Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, China, 3Department of Radiation Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China Purpose/Objective(s): We aimed to evaluate the prognostic value of peripheral immune cells in oligometastatic non-small cell lung cancer (NSCLC) patients who are treated with stereotactic ablative radiotherapy (SABR). Materials/Methods: We enrolled 63 patients with pulmonary recurrencebased oligometastatic NSCLC; all patients’ metastases had been treated with SABR. Peripheral regulatory T cells (CD4+CD25+CD127low), B cells, NK cells, gdT cells, CD8+CD28+ T cells, and CD8+CD28- T cells were evaluated by flow cytometry. Prognostic values of factors were evaluated by Cox proportional hazards regression.

Results: The median follow-up time was 19.1 months. Estimated overall survival (OS) rates at 1, 2, and 3 years were 84.3%, 63.4%, and 44.0%. Estimated progression-free survival (PFS) rates at 1, 2, and 3 years were 55.2%, 30.9%, and 25.7%. Patients with high regulatory T cells (Treg) showed decreased OS and PFS, compared with those with low Treg cells (OS: 16.1 months vs. not reached, P Z 0.006; PFS: 11.0 vs. 21.7 months, P Z 0.006). Treg level is an independent prognostic factor for both OS and PFS in patients with pulmonary recurrence-based oligometastatic NSCLC who were treated with SABR in multivariate analyses (HR Z 2.68, 95% CI: 1.05-6.85, P Z 0.038, and HR Z 2.35, 95% CI: 1.21-4.54, P Z 0.011, respectively). Conclusion: Peripheral Treg level revealed independent prognostic value in patients with pulmonary recurrence-based oligometastatic NSCLC, in which patients were treated with SABR for all metastases. Additional treatments may require combination with SABR following selection of oligometastatic NSCLC patients with poor outcomes. Author Disclosure: C. Liu: None. B. Sun: None. X. Hu: None. J. Yue: None. J. Yu: None.

1023 CX3CR1 Expressing Macrophages Infiltrate the Tumor Microenvironment and Promote Radiation Resistance in a Mouse Model of Lung Cancer T. Ben-Mordechai,1 Y. Lawrence,1,2 Z. Symon,1,2 A. Shimoni-Sebag,1 S. Appel,1 and U. Amit1; 1Radiation Oncology, Sheba Medical Center, Ramat Gan, Israel, 2Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Purpose/Objective(s): Combining radiation and immunotherapy targeting T lymphocytes is extensively studied in lung cancer treatment. Current evidence suggests that only a subset of patients will benefit, while most tumors will eventually develop resistance and progress. Tumor associated macrophages (TAM) are a significant component of the TME capable of both suppressing (M1) and promoting (M2) tumor growth based on their functional state. Chemokine receptor, CX3CR1, plays an important role in macrophage homeostasis and effector functions, however its role in the TME following radiation treatment remains unknown. We hypothesized that macrophages expressing CX3CR1, play a central role in TME after radiation therapy. Materials/Methods: Mouse lung cancer model was performed by subcutaneously inoculating Lewis Lung Carcinoma (LLC) expressing luciferase (Luc-2) and mCherry cells in CX3CR1GFP/GFP reporter mice and CX3CR1DTR/+ mice. Tumor growth was monitored by bioluminescence Imaging and caliper. TME inflammatory composition was assessed by flow cytometry. Clonogenic and HUVEC assays were used to assess tumor survival and angiogenesis after radiation. Results: Ten days after tumor irradiation with 8 Gy, irradiated tumors were smaller than non-treated tumors. In-vivo bioluminescent imaging and flowcytometry demonstrated a significant influx of CX3CR1 expressing cells into the irradiated TME, notably, macrophages (F4/80+ CX3CR1+). To establish the direct effect of CX3CR1 expressing macrophages on tumor growth in-vitro, we performed a clonogenic assay, by co-culturing peritoneal macrophages with irradiated LLC cells. Eliminating CX3CR1 expressing macrophages from the culture (by negative selection), reduced LLC survival fraction by 25% (PZ0.005). Tumor growth is highly dependent on angiogenesis and blood supply. Interestingly, HUVEC assay showed reduced tube formation capability after eliminating CX3CR1 expressing macrophages from the co-culture. Finally, to evaluate CX3CR1 depletion effect in-vivo, we injected LLC-mCherry-Luc2 cells subcutaneously into CX3CR1DTR/+ mice, sensitive to the diphtheria toxin, and C57BL/6J control mice. Two weeks after inoculation, tumors were irradiated with 8Gy, and mice were treated every 3 days with diphtheria toxin, leading to reduction in CX3CR1 expressing cells. Three weeks after radiation, CX3CR1 depleted mice showed reduced tumor growth. Furthermore, flow cytometry analysis showed reduction in pro-tumoral M2 macrophage population (F4/80+CD206+), with no difference in Tlymphocyte or programmed cell death-1 expressing cells.