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Figure S5 from Intragenic Rearrangement Burden Associates with Immune Cell Infiltration and Response to Immune Checkpoint Blockade in Cancer

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posted on 2024-03-04, 21:27 authored by Han Zhang, Sanghoon Lee, Renee R. Muthakana, Binfeng Lu, David N. Boone, Daniel Lee, Xiao-Song Wang

Figure S5. IGR burden correlates with tumor-infiltrating lymphocytes and pro-inflammatory pathways in WGS560 TNBC samples. (a) The distributions of IGR burden in TNBC subtypes. Wilcoxon rank sum tests were conducted to test if the median of IGR burdens in a certain subtype is significantly different than the other subtypes. `*` p<0.05. (b) Scatter plot revealing the association between HRD score (X-axis) and inflame signature (Y-axis), colored according to IGR burden. (c) Boxplots showing the distribution of inflaming signature, total mitoses and HRD score in IGRhigh and IGRlow tumors (samples outside the 10%-90% range are considered outliers). (d) Scatter plot showing the correlation between SCNA and HRD score (Pearson R=0.263, p=0.0008), and between SCNA and T-inflamed signature (Pearson R=-0.037, p=0.76) (e) The p-value for each marker in the multivariate model containing all markers including HRD and different types of genetic markers against T inflamed signature in TNBC tumors, when the confounding effects from other variables are removed. (f) Heatmap displays the normalized expression level of genes important in tumor immunology in TNBC samples. Samples are annotated by mitotic score, tumor grade, TIL and IGR level. (g) Enrichment plots for the pathways of interest as revealed by GSEA.

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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DOD Peer Reviewed Cancer Research Program (PRCRP)

PA breast cancer coalition

Shear Family Foundation (Shear Family Foundation Inc)

Hillman Foundation

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ARTICLE ABSTRACT

Immune checkpoint blockade (ICB) can induce durable cancer remission. However, only a small subset of patients gains benefits. While tumor mutation burden (TMB) differentiates responders from nonresponders in some cases, it is a weak predictor in tumor types with low mutation rates. Thus, there is an unmet need to discover a new class of genetic aberrations that predict ICB responses in these tumor types. Here, we report analyses of pan-cancer whole genomes which revealed that intragenic rearrangement (IGR) burden is significantly associated with immune infiltration in breast, ovarian, esophageal, and endometrial cancers, particularly with increased M1 macrophage and CD8+ T-cell signatures. Multivariate regression against spatially counted tumor-infiltrating lymphocytes in breast, endometrial, and ovarian cancers suggested that IGR burden is a more influential covariate than other genetic aberrations in these cancers. In the MEDI4736 trial evaluating durvalumab in esophageal adenocarcinoma, IGR burden correlated with patient benefits. In the IMVigor210 trial evaluating atezolizumab in urothelial carcinoma, IGR burden increased with platinum exposure and predicted patient benefit among TMB-low, platinum-exposed tumors. Altogether, we have demonstrated that IGR burden correlates with T-cell inflammation and predicts ICB benefit in TMB-low, IGR-dominant tumors, and in platinum-exposed tumors.

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