Radiation Biology

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SU_38_2379 - Mitomycin C Enhances Radiation Effect against Rectal Cancer with Favorable Modulation of Tumor Microenvironment

Sunday, October 21
1:15 PM - 2:45 PM
Location: Innovation Hub, Exhibit Hall 3

Mitomycin C Enhances Radiation Effect against Rectal Cancer with Favorable Modulation of Tumor Microenvironment
Y. S. Chen1, C. W. Chi2, H. R. Shieh2, C. P. Lin2, C. C. Ko2, Y. C. Chung2, S. H. Wu2, and Y. J. Chen1; 1Department of Radiation Oncology, MacKay Memorial Hospital, Taipei, Taiwan, 2Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan

Purpose/Objective(s): Mitomycin C (MMC), a hypoxia-activated prodrug or bioreductive drug, is a standard adjunct to radiotherapy (RT) in anal cancer. Rectal cancer is regarded hypoxic and immunogenic with complexity in tumor microenvironment (TME). Neoadjuvant concurrent chemoradiation (CCRT) is the standard of care for locally advanced rectal cancer. However, the effect of CCRT to achieve complete pathological response remains unsatisfactory. We aimed to evaluate the combinatory effect of MMC and RT on rectal cancer and investigate its putative mechanisms.

Materials/Methods: In vitro hypoxia was induced by 1% O2 culture for CT26 rectal adenocarcinoma cells. HIF-1α expression was examined with Western blotting. Clonogenicity and MTT assays were used for radiation and drug survival. In syngeneic CT26 model, tumors were treated as follows: control, MMC (1–2 mg/kg/day), fractionated RT (fRT) (2 x 2Gy or 3 x 3Gy), and combination with MMC 2h prior to RT. Tumor volume, body weight, and white blood cell (WBC) count were monitored for 1 month. For TME analysis, flow cytometry was used for detection of M1 macrophages (MHC-II+), M2 (CD206+), natural killer cell (NK) (NKG2D+), cytotoxic T cell (CTL) (CD8+), dendritic cell (DC) (CD83+), tumor-infiltrating myeloid cell (TIMC) (CD11b+), total T cell (CD3+), and regulatory T cell (Treg) (FoxP3+). γ-H2AX was quantitated by fluorocytometric analysis and interferon-b1 (Ifnb1) mRNA expression was evaluated by quantitative RT-PCR. IHC staining was performed for PD-1/PD-L1 expression.

Results: Under hypoxic condition verified by upregulated HIF-1α expression, MMC inhibited growth activity and exhibited radiosensitizing effect, resulting in a sensitizer enhancement ratio of up to 3.1 in CT26 cells. MMC also promoted production and delayed repair of DNA double strand break. Expression of Ifnb1 was augmented by fRT and further upregulated with the addition of MMC. In vivo treatment using MMC plus fRT profoundly suppressed tumor growth with durable effect in comparison to MMC or RT alone. Decrease in body weight and WBC count in combination group was moderate and tolerable. In TME analysis, fRT increased intratumoral DCs whereas MMC enhanced M1 macrophages and total T cells to a greater extent. Intriguingly, combination of MMC and fRT markedly recruited CTL and NK cells into tumor and reduced infiltration of Treg, indicating a favorable immunomodulating effect. MMC with hypofractionated RT (3 x 3 Gy) had similar but less prominent effect. Combinatory treatment enhanced PD-L1 and suppressed PD-1 expression in tumor draining lymph node.

Conclusion: Our results implicate the combination of MMC and conventional fRT may have synergistic therapeutic effect accompanied by modulation of TME toward favorable immune-cell lineage commitment. The correlation between impaired DNA repair, upregulated Ifnb1 mRNA expression, and TME alteration is undergoing clarification. Further optimization for combination of MMC and fRT is warranted before translating to clinical research.

Author Disclosure: Y. Chen: None. C. Chi: None. H. Shieh: None. C. Ko: None.

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