Immunotherapy response modeling by ex-vivo organ culture for lung cancer

Kamer, Iris; Bab-Dinitz, Elizabeta; Zadok, Oranit; Ofek, Efrat; Gottfried, Teodor; Daniel-Meshulam, Inbal; Hout‐Siloni, Goni; Nun, Alon Ben; Barshack, Iris; Onn, Amir; Bar, Jair

doi:10.1007/s00262-020-02828-w

Cited by 11 publications

(19 citation statements)

References 43 publications

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“…110 Air-liquid-interface PDOs obtained from different cancer types responded to ex vivo PD-1 blockade by induction of IFN-g. 111 Similar observations have been made following anti-PD-L1 treatment in an ex vivo organ culture system that used fragmented tumor clusters derived from NSCLC specimens. 112 Using a PDE model of patientderived tumor fragments, it was demonstrated that immunological responses captured by T-cell activation as well as the secretion of multiple cytokines and chemokines by the TME can predict clinical responses to PD-1 blockade. 36 Notably, combination of ex vivo cultures with the analysis of baseline tumor properties allowed to distinguish distinct TME subgroups across cancer types that were associated with either response or resistance to PD-1 blockade and to identify predictive markers such as TLS.…”

Section: Preclinical Modeling Of Immunotherapy Responsesmentioning

confidence: 99%

Multimodal predictors for precision immunotherapy

Roelofsen¹,

Kaptein²,

Thommen

2022

Immuno-Oncology and Technology

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Section: Preclinical Modeling Of Immunotherapy Responsesmentioning

confidence: 99%

Multimodal predictors for precision immunotherapy

Roelofsen¹,

Kaptein²,

Thommen

2022

Immuno-Oncology and Technology

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“…Patient-derived lung cancer spheroids were introduced in 2008 by Eramo and coworkers, providing a personalized 3D model able to generate xenografts that recapitulated the histology of parental tumors [ 9 ]. Patient-derived lung cancer spheroids were used for in vitro and in vivo studies by our group and others [ 10 , 11 , 12 , 13 , 14 ], providing a reliable preclinical model for drug testing and molecular analyses. The advent of patient-derived organoids (PDOs) provided a further improvement to tumor modeling in terms of structural complexity, cell differentiation, heterogeneity, and physiological function [ 15 ].…”

Section: A Brief History Of Normal and Neoplastic Lung Organoidsmentioning

confidence: 99%

Lung Cancer Organoids: The Rough Path to Personalized Medicine

Rossi

Angelis

Xhelili

et al. 2022

Cancers

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Lung cancer is the leading cause of cancer death worldwide. Despite significant advances in research and therapy, a dismal 5-year survival rate of only 10–20% urges the development of reliable preclinical models and effective therapeutic tools. Lung cancer is characterized by a high degree of heterogeneity in its histology, a genomic landscape, and response to therapies that has been traditionally difficult to reproduce in preclinical models. However, the advent of three-dimensional culture technologies has opened new perspectives to recapitulate in vitro individualized tumor features and to anticipate treatment efficacy. The generation of lung cancer organoids (LCOs) has encountered greater challenges as compared to organoids derived from other tumors. In the last two years, many efforts have been dedicated to optimizing LCO-based platforms, resulting in improved rates of LCO production, purity, culture timing, and long-term expansion. However, due to the complexity of lung cancer, further advances are required in order to meet clinical needs. Here, we discuss the evolution of LCO technology and the use of LCOs in basic and translational lung cancer research. Although the field of LCOs is still in its infancy, its prospective development will likely lead to new strategies for drug testing and biomarker identification, thus allowing a more personalized therapeutic approach for lung cancer patients.

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“…Indeed, we saw that NSCLC patients with low levels of PSME4 in the tumor had a higher ICI response rate, consistent with the findings in Melanoma, Bladder and Kidney cancer, albeit not significantly due to the small size. To strengthen this observation, we utilized an Ex-Vivo Organoid Culture model (EVOC (Kamer et al, 2021)), which contain tumor tissue, infiltrating lymphocytes and stroma cells (Figure 6G, S26A-B). We assessed the expression of PSME4 and PSMB10 as well as stained for CD8 + T cell infiltrates and PDL1 from a section of the resected tumor (Figure S26A-B).…”

Section: ) (F)mentioning

confidence: 99%

“…(I-K) The amount (pg/ml) of IFNγ (I) , IL-17 (J) or IL-22 (K) secreted from splenic lymphocytes from mice bearing KP1.9 or KP1.9 PSME4 OE tumors (*P<0.05, **P<0.01). levels (Kamer et al, 2021) were then used to define a response-like signature in the EVOCs. Notably, we found that tumors with responder hallmarks had significantly lower PSME4/PSMB10 ratios compared to non-responders (Figures 6H-I, S26C-F) and that neither PSME4 nor PSMB10 individually associated with the response (Figures S26H-I).…”

Section: ) (F)mentioning

confidence: 99%

The proteasome regulator PSME4 drives immune evasion and abrogates anti-tumor immunity in NSCLC

Javitt

Shmueli

et al. 2021

Preprint

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Protein degradation by proteasomes is important for the immune response against tumors. Antigens generated by the proteasome promote immune cell infiltration into tumors and improve tumor response to immunotherapy. For example, immunoproteasomes – a subset of proteasomes induced by inflammatory signals – may improve the response of melanomas to immune checkpoint inhibitors (ICI) by eliciting tumor inflammation. Yet, it is unclear whether and how protein degradation by proteasomes impacts cancer progression and contributes to immune evasion and resistance. Here, we profile the proteasome-cleaved peptides in lung cancers and find that PSME4 serves as a novel inhibitory regulator of the immunoproteasome, playing an anti-inflammatory role in cancer. Biochemical assays combined with scRNA-seq, immunopeptidomics and in vivo analyses demonstrate that PSME4 promotes an immunosuppressive environment around the tumor and abrogates anti-tumor immunity by inhibiting antigen presentation and attenuating tumor inflammation. Furthermore, we find that PSME4 expression is correlated with responsiveness to ICI across several cancer types. Our findings suggest that PSME4-mediated regulation of proteasome activity is a novel mechanism of immune evasion in non-small-cell lung carcinoma and may be targeted therapeutically for restoring anti-tumor immunity.

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Immunotherapy response modeling by ex-vivo organ culture for lung cancer

Cited by 11 publications

References 43 publications

Multimodal predictors for precision immunotherapy

Multimodal predictors for precision immunotherapy

Lung Cancer Organoids: The Rough Path to Personalized Medicine

The proteasome regulator PSME4 drives immune evasion and abrogates anti-tumor immunity in NSCLC

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