TxImmuneOrganoids · Divide and conquer: using patient-derived tumour organoids to dissect intra-tumour immune heterogeneity of non-small cell lung cancer

Divide and conquer: using patient-derived tumour organoids to dissect intra-tumour immune heterogeneity of non-small cell lung cancer

Context The immune system has the capacity to control cancer growth, as illustrated by the recent successes in therapies aimed at reinvigorating anti-tumour immunity. It is becoming increasingly clear that there is heterogeneity within individual tumours with respect to their interaction with the immune system. For example, regions heavily infiltrated with immune cells (‘hot’ regions) and immune-deserted regions (‘cold’ regions) can coexist in the same tumour. At the same time, driven by work from the host (Swanton) lab and other labs, we now know that cancers are subject to the force of genetic evolution, resulting in multiple cancer subclones that harbour distinct genetic mutations. The extent to which separate subclones differ in their capacity for immune evasion, the tumour-intrinsic mechanisms underlying any such heterogeneity, and its impact on cancer immunosurveillance remain largely unexplored. This question has both biological and clinical relevance, as resistance to cancer immunotherapy could be driven by (minor) resistant subclones. Identifying the mechanisms that drive subclonal immune evasion could therefore ultimately lead to the development of novel immunotherapies that will result in deeper responses compared to current practice. Determining the ability of individual cancer subclones to elicit an immune cell response has been challenging so far because of the lack of patient-derived model systems that can recapitulate the interaction between cancer cells and immune cells at the level of single clones. Overall objectives Patient-derived tumour organoids (PDTOs) are three-dimensional cultures of cancer cells that can be established directly from patient tumours. PDTOs can be co-cultured with patient-matched immune cells to create a miniaturised test system for anti-tumour immunity at the level of an individual patient. Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived study platform that allows the evaluation of T-cell responses to individual cancer subclones. Our overall objective is to evaluate whether distinct subclones differ in their ability to elicit a T-cell response, and the mechanistic basis underlying any such heterogeneity (Fig. 1)

Data: CORDIS, © European Union