Genome instability and immune evasion are both defining hallmarks of cancer. Tumorigenesis is frequently initiated when there is DNA damage to a proto-oncogene or tumor suppressor gene and DNA repair mechanisms are lost or insufficient to correct the damage; immune evasion then prevents the host immune system from recognizing these transformed cells. Therapies targeting genomic instability and immune evasion have been effectively used to treat cancer. Genotoxic therapies such as chemoradiation have been employed in cancer treatments for several decades, while immunotherapy is a relatively new class of cancer therapy that has led to disease regression even in patients with advanced cancer. Several recent studies have shown synergy between both classes of therapy targeting these two defining hallmarks of cancer, and different mechanisms are proposed to be involved. Here, we review the different classes of DNA damage, their links to cancer, and their contribution to immunotherapy responses, as well as the different models that are currently being used to study tumor–immune interactions.

Angiosarcomas are rare malignant tumors of the endothelium, arising commonly from the head and neck region (AS-HN) and recently associated with ultraviolet (UV) exposure and human herpesvirus-7 infection. We examined 81 cases of angiosarcomas, including 47 cases of AS-HN, integrating information from whole genome sequencing, gene expression profiling and spatial transcriptomics (10X Visium). In the AS-HN cohort, we observed recurrent somatic mutations in CSMD3 (18%), LRP1B (18%), MUC16 (18%), POT1 (16%) and TP53 (16%). UV-positive AS-HN harbored significantly higher tumor mutation burden than UV-negative cases (p = 0.0294). NanoString profiling identified three clusters with distinct tumor inflammation signature scores (p < 0.001). Spatial transcriptomics revealed topological profiles of the tumor microenvironment, identifying dominant but tumor-excluded inflammatory signals in immune-hot cases and immune foci even in otherwise immune-cold cases. In conclusion, spatial transcriptomics reveal the tumor immune landscape of angiosarcoma, and in combination with multi-omic information, may improve implementation of treatment strategies.

Idiopathic Multicentric Castleman Disease (iMCD) is a rare IL-6-driven hematological disorder characterized by systemic lymphadenopathy, elevated immunoglobulin levels, and prominent plasmacytosis in the bone marrow and lymph nodes. An unusual occurrence of iMCD in identical twins provided a unique opportunity to answer genetic and molecular features of this disease, including the cell-of-origin of IL-6 signals, and the immune milieu within affected lymphoid organs and in circulation. Germline whole genome sequencing of the affected twins identified pathogenic homozygous mutations of NCOA4 c.G1322A and monoallelic mutations of TRAF3 c.G1504A - both genes recently implicated in IL-6 signaling and B-cell regulation. Their unaffected sister was heterozygous mutant for NCOA4 and homozygous wildtype for TRAF3 loci. Via single cell sequencing of 63,519 cells from bone marrow, lymph node, and peripheral blood mononuclear cells, we identified nodal endothelial cells and fibroblastic reticular cells (FRC) as the source of IL-6 signals. The latter are composed of mainly T-cell zone FRCs (CCL19+/CCL21+/IL7+/PDPN+/MADCAM1-) and a minor population of follicular dendritic cells (FDCs) (CD21+/CD35+/CXCL13+). An “inflammatory” peripheral monocytosis enriched for the expression of S100A family genes was evident in both twins, as well as a group of monocytes expressing cytotoxic gene signatures in the affected twin with milder clinical manifestations. Their unaffected sister mainly carried monocytes enriched for expression of major histocompatibility complex (MHC) class II genes. In conclusion, we provided evidence of a genetic cause of iMCD, identified the putative cell-of-origin of IL-6 signals in this rare disease, and described a distinct monocytic immune response phenotype. Citation Format: Jason Yongsheng Chan, Jui Wan Loh, Jing Quan Lim, Herty Liany, Elizabeth Chun Yong Lee, Jing Yi Lee, Bavani Kannan, Boon Yee Lim, Kerry Lim, Jeslin Chian Hung Ha, Cedric Chuan-Young Ng, Tun Kiat Ko, Dachuan Huang, Dominique Yuan Bin Seow, Chee Leong Cheng, Sock Hoai Chan, Joanne Ngeow, Bin Tean Teh, Soon Thye Lim, Choon Kiat Ong. Single cell landscape of multicentric Castleman disease in identical twins. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4458.

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