64 - Freie Mitteilung
16. Mai 2019, 13:45 - 15:15, Szenario 1, 5. OG
Induction of anticancer immune responses: Novel insights in mechanisms of hyperthermic intraperitoneal chemotherapy (HIPEC)
L. Roth, E. Breuer, R. Graf, P.-A. Clavien, A. Gupta, K. Lehmann, Presenter: L. Roth (Zürich)
Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improved survival of selected patients with peritoneal metastasis from colorectal cancer. However, peritoneal recurrence is common and it is important to understand mechanisms operating behind HIPEC for further improvements. We hypothesized that the combination of chemotherapy and heat might not only be cytotoxic, but may also induce strong immunogenic changes within the tumor microenvironment. We therefore assessed effects of Mitomycin C/Doxorubicin (M/D) and Oxaliplatin (Oxa), widely used in the clinical setting, on the expression of immunogenic cancer-testis antigens (CTAs) on cancer cells after treatment with HIPEC-like conditions and subsequent monocyte-derived dendritic cell (Mo-DC) maturation and CD 8+T-cell activation.
Multiple colorectal cell-lines were treated with M/D or Oxa for 30 minutes +/- hyperthermia (430C). 72 hours after treatment, CTA expression was analyzed using qPCR and western blot. To assess Mo-DC maturation and CD8+ T-cell activation, we set up co-cultures with colorectal cells, Mo-DC`s and purified CD 8+ T-cells. We analyzed surface markers such as HLA-DR and CD 83 to assess Mo-DC maturation, and measured CD8+ T-cell activation via intracellular IFN-y staining using flow cytometry.
HIPEC treatment induced de-novo expression of two CTAs, Cyclin A1 and SSX-4. Compared to controls (no drug, 370C), M/D at hyperthermic condition increased Cyclin A1 by 53 folds and SSX-4 by 30 folds, similar to Oxa treated tumor cells. On protein level, Cyclin A1 was highly increased compared to control treatment (p=0.004). Mo-DC`s, after co-culturing with HIPEC treated colorectal cancer cells, significantly expressed maturation markers CD83 and HLA-DR. Furthermore, Mo-DC`s after activation by co-culture with HIPEC-treated cancer cells, were able to prime CD8+ T-cells, leading to enhanced IFN-y production by CD8+ T cells.
HIPEC treatment induces immunogenic changes in colorectal cancer cells and leads to Mo-DC maturation and subsequent CD8+ T-cell activation. These novel insights may explain observed long-term effect in selected patients, and represent a novel aspect of HIPEC, beyond cytotoxicity.