A high tumour mutational burden (TMB) generally correlates with better responses to antitumour immunotherapy. However, there are many exceptions and recent studies have shown that intratumoural heterogeneity (ITH) also plays a role in shaping antitumour immune responses. Now, reporting in Cell, Wolf et al. present a mouse model of melanoma in which both TMB and ITH can be titrated and show that ITH is a better predictor for immunotherapy outcome than TMB.
First, the authors exposed B2905 mouse melanoma cells to UVB irradiation, a major carcinogen that increases the TMB. UVB-treated cells grew more slowly in culture but formed fast-growing tumours when injected into mice. They also showed a poor response to anti-PD1 checkpoint blockade.
In order to tease apart the functional effects of TMB and ITH, single-cell-derived clones were generated from the UVB treated cells and their TMB was determined by exome sequencing. Independent of their individual TMB, the clones grew at a dramatically reduced rate when injected into mice, resolving spontaneously within a few weeks. However, when injected into immunocompromised mice (NSG mice or CD80–/–/CD86–/– mice), they grew at the same rate as unselected UVB-irradiated B2905 cells, indicating that clone-derived tumours (with an inherently low ITH) are rejected by the immune system. Further experiments showed that a decreased ITH led to enhanced T cell reactivity and tumour infiltration.
The effects of ITH and TMB were then investigated using phylogenetic analysis and experiments in which different clones were mixed. These demonstrated that both the number of subclones within the tumour and the degree of their genetic diversity determine tumour growth and immune rejection.
Next, the authors analysed patient data from cohorts of patients who had undergone checkpoint inhibitor therapy. They found that patients with more diverse tumours (both in terms of the number of clones within the tumour and the genetic diversity between the clones) showed poorer survival.
One could assume that tumours with a high ITH might be better protected from the immune response because of the outgrowth of ‘escape’ clones. However, when analysing UVB-irradiated B2905 tumours in mice over time, the authors found no change in their clonal composition, indicating that no such outgrowth occurs. Instead, they propose that tumours with a high ITH can escape immune surveillance because particular tumour neoantigens undergo ‘dilution’ within the tumour, thereby leading to weaker antitumour immunity and less immune cell infiltration.
“the number of subclones within the tumour and the degree of their genetic diversity determine tumour growth and immune rejection”
Although the mechanisms underlying the modulation of antitumour immunity by ITH require further investigation, this study shows that assessing the ITH in melanoma patients might be useful as a prognostic indicator for response to immunotherapy. Moreover, it indicates that antigen-specific immunotherapy approaches need to be targeted at antigens present in a large number of clones and that agents that increase the TMB may also increase tumour heterogeneity, which should be avoided.
Wolf, Y. et al. UVB-induced tumor heterogeneity diminishes immune response in melanoma. Cell 179, 219–235 (2019)
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Flemming, A. Tumour heterogeneity determines immune response. Nat Rev Immunol 19, 662–663 (2019). https://doi.org/10.1038/s41577-019-0230-8
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