“…Different approaches were employed including patient-derived tumor xenograft (PDX) models, combination of mouse models with state-of-the-art imaging techniques such as high-resolution intravital microscopy, organoid development, and patient-derived tumor fragment (PDTF) platforms (Fig. 5a ) 36 – 39 . Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Organoid co-culture models from tumor and non-tumor UPTIDER samples to study the interaction dynamics between cancer cells and their host tissues will be established too. Finally, a patient-derived tumor fragment (PDTF) platform, where cellular composition and spatial organization from the original lesion can be maintained, has been set-up with the Thommen laboratory (Netherlands Cancer Institute) 39 , 43 , 44 . This platform will be used to test and compare multiple (new) treatment strategies, to directly link treatment responses to intra-patient inter-lesion heterogeneity and to provide new insights into response and resistance mechanisms.…”
Research on metastatic cancer has been hampered by limited sample availability. Here we present the breast cancer post-mortem tissue donation program UPTIDER and show how it enabled sampling of a median of 31 (range: 5-90) metastases and 5-8 liquids per patient from its first 20 patients. In a dedicated experiment, we show the mild impact of increasing time after death on RNA quality, transcriptional profiles and immunohistochemical staining in tumor tissue samples. We show that this impact can be counteracted by organ cooling. We successfully generated ex vivo models from tissue and liquid biopsies from distinct histological subtypes of breast cancer. We anticipate these and future findings of UPTIDER to elucidate mechanisms of disease progression and treatment resistance and to provide tools for the exploration of precision medicine strategies in the metastatic setting.
“…Different approaches were employed including patient-derived tumor xenograft (PDX) models, combination of mouse models with state-of-the-art imaging techniques such as high-resolution intravital microscopy, organoid development, and patient-derived tumor fragment (PDTF) platforms (Fig. 5a ) 36 – 39 . Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Organoid co-culture models from tumor and non-tumor UPTIDER samples to study the interaction dynamics between cancer cells and their host tissues will be established too. Finally, a patient-derived tumor fragment (PDTF) platform, where cellular composition and spatial organization from the original lesion can be maintained, has been set-up with the Thommen laboratory (Netherlands Cancer Institute) 39 , 43 , 44 . This platform will be used to test and compare multiple (new) treatment strategies, to directly link treatment responses to intra-patient inter-lesion heterogeneity and to provide new insights into response and resistance mechanisms.…”
Research on metastatic cancer has been hampered by limited sample availability. Here we present the breast cancer post-mortem tissue donation program UPTIDER and show how it enabled sampling of a median of 31 (range: 5-90) metastases and 5-8 liquids per patient from its first 20 patients. In a dedicated experiment, we show the mild impact of increasing time after death on RNA quality, transcriptional profiles and immunohistochemical staining in tumor tissue samples. We show that this impact can be counteracted by organ cooling. We successfully generated ex vivo models from tissue and liquid biopsies from distinct histological subtypes of breast cancer. We anticipate these and future findings of UPTIDER to elucidate mechanisms of disease progression and treatment resistance and to provide tools for the exploration of precision medicine strategies in the metastatic setting.
“…Next, we aimed to address the potential of CD8–IL2 to reinvigorate tumor-infiltrating CD8 + T cells in their native tissue context, using a recently developed PDTF platform ( 10 , 33 ). PDTFs are 3D fragments of human tumor tissue preserving the TME contexture outside of the patient and allowing short-term ex vivo culture in the absence or presence of immunotherapies.…”
Section: Resultsmentioning
confidence: 99%
“…PDTF cultures were performed as described previously ( 10 , 33 ). In brief, cryopreserved PDTFs were thawed and washed with wash medium [Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% FCS and 1% penicillin–streptomycin].…”
Section: Methodsmentioning
confidence: 99%
“…We here explored a novel IL2 molecule targeted to CD8β (CD8–IL2) that allows the selective stimulation of the CD8 + T cells critical for tumor control, while minimizing the activation and amplification of immunosuppressive Tregs and of other cell types such as NK cells that may contribute to systemic toxicity ( 32 ). Utilizing the patient-derived tumor fragment (PDTF) platform ( 10 , 33 ) that provides a tumor microenvironment (TME) context that closely resembles the one present in patients with cancer, we assessed (i) whether CD8–IL2 can induce T-cell activation in human tumors and which specific cell types and cell states are responsive to this treatment; (ii) how CD8–IL2 reinvigorates antitumor T-cell immunity, and (iii) how T-cell reactivation upon CD8–IL2 differs from that achieved upon PD-1 blockade. Our data demonstrate that CD8–IL2 broadly arms tumor-infiltrating CD8 + T cells with effector capacity.…”
Tumor-specific CD8+ T cells are key effectors of antitumor immunity but are often rendered dysfunctional in the tumor microenvironment. Immune checkpoint blockade can restore antitumor T cell function in some patients, however most do not respond to this therapy, often despite T cell infiltration in their tumors. We here explored a CD8-targeted IL2 fusion molecule (CD8-IL2) to selectively reactivate intratumoral CD8+ T cells in patient-derived tumor fragments. Treatment with CD8-IL2 broadly armed intratumoral CD8+ T cells with enhanced effector capacity, thereby specifically enabling reinvigoration of the dysfunctional T cell pool to elicit potent immune activity. Notably, the revival of dysfunctional T cells to mediate effector activity by CD8-IL2 depended on simultaneous antigen recognition and was quantitatively and qualitatively superior to that achieved by PD-1 blockade. Finally, CD8-IL2 was able to functionally reinvigorate T cells in tumors resistant to anti-PD-1, underscoring its potential as a novel treatment strategy for cancer patients.
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