Evolution of Metastases in Space and Time under Immune Selection

Abstract

We examined how the immune microenvironment molds tumor evolution at different metastatic organs in a longitudinal dataset of colorectal cancer. Through multiplexed analyses, we showed that clonal evolution patterns during metastatic progression depend on the immune contexture at the metastatic site. Genetic evidence of neoantigen depletion was observed in the sites with high Immunoscore and spatial proximity between Ki67 + tumor cells and CD3 + cells. The immunoedited tumor clones were eliminated and did not recur, while progressing clones were immune privileged, despite the presence of tumor-infiltrating lymphocytes. Characterization of immune-privileged metastases revealed tumor-intrinsic and tumorextrinsic mechanisms of escape. The lowest recurrence risk was associated with high Immunoscore, occurrence of immunoediting, and low tumor burden. We propose a parallel selection model of metastatic progression, where branched evolution could be traced back to immune-escaping clones. The findings could inform the understanding of cancer dissemination and the development of immunotherapeutics.

Invasion of homogeneous and polyploid populations in nutrient-limiting environments

“…Infiltrating and invasive phenotypes are often observed among high-ploidy cells. Converging evidence from different cancer types, including colorectal-, breast-, lung-and brain cancers, suggests a strong enrichment of high ploidy cells among metastatic lesions as compared to the primary tumor [14,15]. Even in normal development: trophoblast giant cells -the first cell type to terminally differentiate during embryogenesis -are responsible for invading the placenta and these cells often have hundreds of copies of the genome [16].…”

A MAP of tumor-host interactions in glioma at single cell resolution

“…The composition of the various cell types making up the microenvironment can significantly affect the way in which the immune system activates cancer rejection mechanisms (Bedognetti et al, 2016; Joyce and Fearon, 2015; Zhang et al, 2019) and influences the response to immune therapies (Ceccarelli et al, 2016; Cristescu et al, 2018). Therefore, the elucidation of the tumor-host interaction mechanisms plays a crucial role in the understanding of the tumor growth and evolution (Angelova et al, 2018; Bedognetti et al, 2019) and for the identification immuno-oncology therapeutic targets (Hoos, 2016). Immune checkpoint inhibitor (ICI) therapies are aimed to targeting the specific cell-cell interaction between PD1 and PD-L1 or CTLA4 and B7-1/B7-2 (Pardoll, 2012).…”

Drug resistance evolution in HIV in the late 1990s: hard sweeps, soft sweeps, clonal interference and the accumulation of drug resistance mutations

“…Given that soft sweeps from recurrent mutation happen (which means that the rate of input of new mutations in the population must be fairly high) and that simultaneous sweeps happen (suggesting that mutations can stay linked), it appears likely that clonal interference also happens in adapting HIV populations. We show Muller plots (Muller, 1932) or evolvograms (Angelova et al, 2018) for several examples, where we think that clonal interference is occurring.…”