“In all disorder a secret order”- intratumoural immune heterogeneity as a hallmark of tumour evolution

An multiomics approach showing heterogeneity in the phenotypes and physiological locations of various immune subsets within each single tumour as a hallmark of tumour evolution and progression in liver cancer

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The genomic heterogeneity and its link to tumor evolution was previously described1 including in hepatocellular carcinoma (HCC)2,3 and given the intimate relationship between tumour cells and its microenvironment, we always wonder if similar evolution also occurs within the tumour immune landscapes. This idea came into light when we first looked at our immune profiling data from multiple HCC tumour sectors and realized just how heterogeneous they are.

Curious and intrigued, our team discussed this intratumoural heterogeneity in the immune landscapes (Immune-ITH) as an interesting phenomenon that must have important implications and link to the tumour evolution. What follows was a lengthy discussion and debates with our genomic and clinical collaborators over whether this immune-ITH would have any true biological meanings at all. With our enthusiasm and tireless pursuits, they were convinced to look into the matched tumour genomic and transcriptomic data which eventually have shown a strong link with the immune-ITH.

The euphorically moment came when we successfully showed, even with the data from less than 20 patients, a strong relationship with tumour mutation burdens, particularly with the neoantigen loads, and the tumour progression in terms of shorter recurrence-free survival in patients with higher immune-ITH. Our collaborators then started to express their keen interest and took our theories seriously. At this point, we could say the rest is history, but not quite yet. We went into a lengthy process to robustly test our hypothesis by including more patients: 28 patients with a total of 95 tumours sectors from our cohort as well as two external public HCC cohorts. We also examined other parameters to explain this immune-ITH phenomenon, discovering how this “co-evolution” was driven by a stronger immuno-selective pressure at earlier stage of tumours, which eventually escape via immunoediting and losing the antigen-presentation capability that finally resulted in immune-ITH, immunosuppression and tumour progression (see figure).

Now here we are presenting our study deciphering the relevance of immune-ITH in terms of its immune subsets phenotypes and physiological locations within each single tumour as the “hallmark” of tumour evolution and progression (https://www.nature.com/articles/s41467-020-20171-7)4. The correlation of immune-ITH and its matched tumour trancriptome indicates the role of intrinsic tumor factors in shaping the heterogeneous intratumoral immune landscape. Our findings highlight the inadequacy of single tumor biopsy and potentially explaine the complexity of clinical responses to immunotherapy as observed clinically 

This study shows to us that despite the initial hurdle we faced with almost as if speaking a “foreign language” to our collaborators from completely different background and expertise, through science we could break all barriers. It was in the end a fruitful collaboration with tremendous fun and excitement walking through the discoveries. 

Finally, we would like to cite a quote from Carl Jung that beautifully summed up our findings: "In all chaos there is a cosmos, in all disorder a secret order”.


1          de Bruin, E. C. et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 346, 251-256, doi:10.1126/science.1253462 (2014).

2          Xue, R. et al. Variable Intra-Tumor Genomic Heterogeneity of Multiple Lesions in Patients With Hepatocellular Carcinoma. Gastroenterology 150, 998-1008, doi:10.1053/j.gastro.2015.12.033 (2016).

3          Zhai, W. et al. The spatial organization of intra-tumour heterogeneity and evolutionary trajectories of metastases in hepatocellular carcinoma. Nat Commun 8, 4565, doi:10.1038/ncomms14565 (2017).

4          Nguyen, P., Ma, S. et al. Intratumoural immune heterogeneity as a hallmark of tumour evolution and progression in hepatocellular carcinoma. Nat Commun12, 227 (2021). https://doi.org/10.1038/s41467-020-20171-7.

Valerie Chew

Principal Investigator, Duke-NUS Medical School

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