Project description
A holistic view on cancer immune evasion
Understanding anti-tumour immunity is central for the design of effective immunotherapy strategies. However, the clonal nature of tumours leads to heterogeneity in treatment response and even drug resistance. Scientists of the EU-funded TxImmuneOrganoids project propose to address this challenge through the development of appropriate patient-derived models. They will establish organoids from non-small cell lung cancer (NSCLC) patients and study their interaction with autologous or allogeneic T cells. Results will provide a holistic and mechanistic overview of immune surveillance and evasion in NSCLC. Moreover, identification of putative molecular determinants may open opportunities for novel anti-cancer interventions.
Objective
Immune checkpoint blockade (ICB) has revolutionised treatment of patients with non-small cell lung cancer (NSCLC), but is effective in only ~20% of patients. Anti-tumour immunity is highly heterogeneous within tumours, and intra-tumour heterogeneity (ITH) is a major driver for treatment resistance. However, the mechanistic basis of intra-tumour immune heterogeneity (ITIH) is unclear, largely due to the absence of appropriate functional models.
Here, I aim to identify the genetic or transcriptomic drivers of ITIH, and their impact on immune surveillance and control. I have recently developed an organoid – T-cell co-culture system that I will use to generate personalised models of ITIH. Leveraging the TRACERx lung cancer evolution study, I will establish multiple clonal organoid lines from the same tumour from NSCLC multi-region biopsies. Each organoid subline will be co-cultured with autologous T-cells to evaluate how they differ in sensitivity to T-cells. For each patient, the 6 most sensitive and 6 most resistant sublines will be used for DNA and RNA sequencing to identify mutations (including neo-antigens), copy number alterations and differentially expressed genes associated with resistance to T-cells. Candidate subclonal immune evasion factors will be validated in organoids by CRISPR-Cas9. I will prioritise genes by cross-referencing with genes associated with immune-cold regions in the TRACERx cohort. I will also perform pooled enrichment screens as a less biased approach.
The integration of novel organoid technology with ‘big data’ from TRACERx allows moving beyond merely descriptive studies of ITIH. This will result in the most fine-grained mechanistic study of ITIH to date.
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Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
NW1 1AT London
United Kingdom