Abstract 1115: Patient-derived explant cultures (PDECs) as a model system for immuno-oncology studies

Abstract

Abstract Despite the great promise of immunotherapy, only relatively few patients show long-term complete remission. In addition, immunotherapy is not effective against every cancer type. Cancer types with low mutational burden such as breast cancer (BCa), for example, are thought to not elicit an immune reaction and are therefore considered non-immunogenic. A major hurdle in the advancement of immunotherapy is the lack of preclinical models that faithfully preserve the tumor microenvironment and recapitulate human disease. We have developed a method to grow 3D cultures of intact fragments of patient-derived tissue (Patient-Derived Explant Cultures; PDECs), which has been used to assess the efficacy of novel treatment regimens on real human tumors (Haikala et al., Nature Comm. 2019; Tervonen et al., Oncogene 2016). PDECs offer many advantages over other cancer model systems; PDECs preserve the human tumor microenvironment, reflect inter- and intra-patient tumor heterogeneity and results are obtained within one week. Up to 16 experimental samples can be obtained from one clinical sample, allowing the same ‘patient' to be experimentally treated with different drug regimens and/or measurement of more than one endpoint.To assess whether PDECs are also a suitable model for IO studies we performed immunoprofiling experiments using FACS, RT-PCR, cytokine profiling and immunofluorescence, showing that the immune-contexture, i.e. the number and activation status of different immune cell types, is similar in PDECs than in the primary tumor they were derived from. Subsequently, we addressed whether the resident immune cells in PDECs were functional. Preliminary data showed that direct T cell activation in PDECs led to apoptosis of cancer cells and invoked a complex immune response, as assessed using cytokine profiling and FACS. Treatment with the immune checkpoint inhibitor anti-PD-1 had more moderate effects. These data reflect the clinical reality where very few BCa patients respond to immune checkpoint monotherapy, but also show that T cells in BCa can be activated to kill the cancer cells, suggesting that with the right treatment strategies, BCa can be targeted with immunotherapy. All in all, our data show that the tumor's immunocontexture is conserved in PDECs and that resident immune cells in PDECs can be activated to attack cancer cells, and thus support the use of PDECs as an ex vivo model system to study immuno-oncology in real human cancers for the development of the immunotherapies of tomorrow. Citation Format: Rita Turpin, Pauliina Munne, Ilida Suleymanova, Satu Mustjoki, Jeroen Pouwels, Juha Klefström. Patient-derived explant cultures (PDECs) as a model system for immuno-oncology studies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1115.