Whole-Genome Doubling And Immune Responses
==Whole genome doubling tends to make tumors more able to evade immune attack rather than less.==[:cite[1]{ln=3}][:cite[2]{ln=4}] Here’s the plain English version: WGD+ tumors had fewer immune cells overall in the...
==Whole genome doubling tends to make tumors more able to evade immune attack rather than less.==[:cite[1]{ln=3}][:cite[2]{ln=4}] Here’s the plain English version: WGD+ tumors had fewer immune cells overall in the tumor, including fewer leukocytes, fewer CD3+ T cells, fewer CD8+ T cells, and a lower CD8/Treg ratio in the mouse model.[:cite[3]{ln=3}] WGD+ tumors also had fewer NK cells, macrophages, and dendritic cells , while neutrophils were higher .[:cite[3]{ln=4}] In human breast cancer cohorts, WGD+ tumors showed lower immune infiltration scores overall .[:cite[5]{ln=3}][:cite[4]{ln=3}] ==The key functional change is that WGD+ cancer cells become worse at showing themselves to the immune system.==[:cite[1]{ln=4}][:cite[2]{ln=5}] More specifically: WGD+ cancer cells had lower expression of antigen presentation genes in immunocompetent mice.[:cite[6]{ln=1}] Cell to cell signaling analysis showed reduced MHC I interactions between cancer cells and CD8+ T cells in WGD+ tumors.[:cite[7]{ln=3}] In human TNBC datasets, WGD+ tumors had lower antigen presentation scores , with reduced expression of some MHC related genes such as B2M and HLA E .[:cite[8]{ln=2}][:cite[8]{ln=4}] In paired human metastases, the WGD+ lesion had reduced T cell infiltration and lower HLA gene and B2M expression in cancer cells.[:cite[9]{ln=2}] ==Why does that matter? Because CD8+ T cells depend on antigen presentation through MHC I to recognize and kill tumor cells.==[:cite[7]{ln=3}][:cite[7]{ln=6}] The paper backs that up experimentally: When the authors knocked out B2m , a key part of MHC I, WGD tumors grew faster, but WGD+ tumors did not change much.[:cite[7]{ln=4}][:cite[7]{ln=5}] That same B2m loss also reduced CD8+ T cell infiltration and lowered the CD8/Treg ratio in WGD tumors.[:cite[7]{ln=6}] ==The paper says this loss of antigen presentation is tied to a weaker IFNγ response in WGD+ cells.==[:cite[1]{ln=4}][:cite[10]{ln=2}] Evidence for that: WGD+ cells showed a diminished response to IFNγ stimulation when B2M surface expression was used as the readout.[:cite[11]{ln=3}] In patient derived organoids, WGD+ samples showed a trend toward reduced induction of HLA and B2M after IFNγ treatment .[:cite[9]{ln=3}][:cite[9]{ln=4}] In human tumor cell data, WGD+ tumors had lower IFNγ response pathway scores and lower expression of IRF1, IRF3, IRF7, STAT1, and NFKB1 .[:cite[12]{ln=1}] ==The paper’s main mechanism is epigenetic: WGD+ cells close off immune related genes in chromatin.==[:cite[2]{ln=5}][:cite[10]{ln=2}][:cite[10]{ln=3}] What changed mechanistically: WGD+ cancer cells lost chromatin accessibility at sites linked to downregulated genes , and those downregulated genes were enriched for immune pathways including IFN signaling .[:cite[13]{ln=2}][:cite[13]{ln=3}] Antigen presentation genes such as H2 d1 and H2 k1 showed reduced ATAC signal in WGD+ cells.[:cite[13]{ln=4}] WGD+ cells had higher H3K27me3 , a repressive histone mark.[:cite[14]{ln=3}] WGD+ cells also had more H3K27me3 peaks overall, but not specifically at the H2k1 and B2m promoters, which suggests the repression is mediated through upstream regulators rather than direct silencing of those MHC I genes themselves.[:cite[15]{ln=2}][:cite[15]{ln=4}][:cite[15]{ln=5}] Motif analysis linked those H3K27me3 changes to reduced accessibility for IRF3 and STAT1 , and WGD+ cells had lower expression of Jak2, Stat1, and Nlrc5 at day 14.[:cite[16]{ln=1}][:cite[16]{ln=3}] ==The metabolic link is that WGD+ tumors had lower KDM6 activity, likely because succinate was higher.==[:cite[1]{ln=5}][:cite[2]{ln=6}][:cite[10]{ln=3}] The paper reports: KDM6A/B protein levels were not significantly different, but KDM6 enzymatic activity was markedly lower in WGD+ tumors, while PRC2 activity was essentially unchanged .[:cite[12]{ln=2}][:cite[12]{ln=3}] KDM6A/B are αKG dependent histone demethylases whose activity is inhibited by succinate .[:cite[17]{ln=2}] WGD+ tumors had significantly higher succinate , and WGD+ cancer cells had lower expression of succinate dehydrogenase subunits .[:cite[17]{ln=3}][:cite[17]{ln=5}] So the chain the paper supports is: ==WGD → higher succinate / lower KDM6 activity → more H3K27me3 and less accessible chromatin at immune regulatory programs → weaker IFNγ response regulators and weaker antigen presentation → poorer CD8+ T cell recognition and a colder immune microenvironment.==[:cite[1]{ln=4}][:cite[1]{ln=5}][:cite[10]{ln=2}][:cite[10]{ln=3}][:cite[16]{ln=1}][:cite[16]{ln=3}][:cite[7]{ln=3}] One important nuance: Early on, WGD+ tumors were not immediately immune cold ; at day 8 they actually showed more leukocytes and T cells and higher IFN related signals, but by day 14 that pattern reversed.[:cite[19]{ln=2}][:cite[18]{ln=6}][:cite[20]{ln=2}][:cite[20]{ln=4}] The authors interpret this as possible immune editing or selection , where WGD+ tumors later b...