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Single-cell DNA sequencing (scDNA-seq) enables decoding somatic cancer variation. Existing methods are hampered by low throughput or cannot be combined with transcriptome sequencing in the same cell. We propose HIPSD&R-seq (HIgh-throughPut Single-cell Dna and Rna-seq), a scalable yet simple and accessible assay to profile low-coverage DNA and RNA in thousands of cells in parallel. Our approach builds on a modification of the 10X Genomics platform for scATAC and multiome profiling. In applications to human cell models and primary tissue, we demonstrate the feasibility to detect rare clones and we combine the assay with combinatorial indexing to profile over 17,000 cells., Competing Interests: Declarations. Ethics approval and consent to participate: Informed consent was obtained for donation of skin biopsies and for patient-derived xenografts from medulloblastoma according to the Declaration of Helsinki and after approval by the ethics committees of the University of Texas M. D. Anderson Cancer Center and Heidelberg University, respectively. Consent for publication: Not applicable. Competing interests: O.S. is a paid consultant of Insitro.Inc. All remaining authors declare that they have no competing interests., (© 2024. The Author(s).)

Dendritic cells (DCs) are crucial for initiating protective immune responses and have also been implicated in the generation and regulation of Foxp3 + regulatory T cells (Treg cells). Here, we show that in the lamina propria of the small intestine, the alternative NF-κB family member RelB is necessary for the differentiation of cryptopatch and isolated lymphoid follicle-associated DCs (CIA-DCs). Moreover, single-cell RNA sequencing reveals a RelB-dependent signature in migratory DCs in mesenteric lymph nodes favoring DC-Treg cell interaction including elevated expression and release of the chemokine CCL22 from RelB-deficient conventional DCs (cDCs). In line with the key role of CCL22 to facilitate DC-Treg cell interaction, RelB-deficient DCs have a selective advantage to interact with Treg cells in an antigen-specific manner. In addition, DC-specific RelB knockout animals show increased total Foxp3 + Treg cell numbers irrespective of inflammatory status. Consequently, DC-specific RelB knockout animals fail to mount protective Th2-dominated immune responses in the intestine after infection with Heligmosomoides polygyrus bakeri. Thus, RelB expression in cDCs acts as a rheostat to establish a tolerogenic set point that is maintained even during strong type 2 immune conditions and thereby is a key regulator of intestinal homeostasis., (© 2024. The Author(s).)

Background: Immune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%-46%. However, irMyocarditis can be asymptomatic. Thus, improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis and assess outcomes in cancer centers with intensified patient management., Methods: Patients with cardiac irAEs from the SERIO registry (www.serio-registry.org) were analyzed for demographics, ICI-related information (type of ICI, therapy line, combination with other drugs, onset of irAE, and tumor response), examination results, irAE treatment and outcome, as well as oncological endpoints. Cardiac biopsies of irMyocarditis cases ( n  = 12) were analyzed by Nanostring and compared to healthy heart muscle ( n  = 5) and longitudinal blood sampling was performed for immunophenotyping of irMyocarditis-patients ( n  = 4 baseline and n  = 8 during irAE) in comparison to patients without toxicity under ICI-therapy ( n  = 4 baseline and n  = 7 during ICI-therapy) using flow cytometry., Results: A total of 51 patients with 53 cardiac irAEs induced by 4 different ICIs (anti-PD1, anti-PD-L1, anti-CTLA4) were included from 12 centers in 3 countries. Altogether, 83.0% of cardiac irAEs were graded as severe or life-threatening, and 11.3% were fatal (6/53). Thus, in centers with established consequent troponin monitoring, work-up upon the rise in troponin and consequent treatment of irMyocarditis with corticosteroids and -if required-second-line therapy mortality rate is much lower than previously reported. The median time to irMyocarditis was 36 days (range 4-1,074 days) after ICI initiation, whereas other cardiotoxicities, e.g. asystolia or myocardiopathy, occurred much later. The cytokine-mediated signaling pathway was differentially regulated in myocardial biopsies as compared to healthy heart based on enrichment Gene Ontology analysis. Additionally, longitudinal peripheral blood mononuclear cell (PBMC) samples from irMyocarditis-patients indicated ICI-driven enhanced CD4+ Treg cells and reduced CD4+ T cells. Immunophenotypes, particularly effector memory T cells of irMyocarditis-patients differed from those of ICI-treated patients without side effects. LAG3 expression on T cells and PD-L1 expression on dendritic cells could serve as predictive indicators for the development of irMyocarditis., Conclusion: Interestingly, our cohort shows a very low mortality rate of irMyocarditis-patients. Our data indicate so far unknown local and systemic immunological patterns in cardiotoxicity., Competing Interests: LH received speaker and consultancy fees from BiomeDx, BMS, Immunocore, Kyowa Kirin, Merck, MSD, Myoncare, Novartis, Pieris, Pierre-Fabre, Roche, Sanofi, Stemline Therapeutics, SUN and Therakos. The LMU received research grants or clinical study grants from Agenus, AstraZeneca Inc., BMS, Hoffmann-La Roche AG, Huya Bioscience, Immunocore, IO Biotech, Merck, Merck Sharp & Dome GmbH, Miltenyi Biomedicine GmbH, Novartis, Pfizer, Pierre Fabre, Regeneron, Replimune, and Sanofi Aventis. CE reports on speaker fees from BristolMyers Squibb, GSK, Immunocore, Kyowa Kirin, MSD CL received honoraria (lectures, presentations, speakers bureaus, manuscript writing or educational events) and travel support from: BMS, MSD Merck, Pierre-Fabre, Biontech, Almirall Hermal, Sun Pharma, KyowaKirin, Immunocore, Sanofi, Novartis. DT reports consultancy, speaker fees or travel grants: BMS, Roche, Novartis, Sanofi, Recordati, Kyowa Kirin, Sun Pharma and Pierre Fabre. LZ served as consultant and has received honoraria from BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Pierre Fabre, Sanofi, Sunpharma and Novartis, outside the submitted work. PJB reports research funding (inst) by BeiGene, BMS, MSD and Takeda; an advisory role to BeiGene, BMS, MSD, Need Inc., Stemline and Takeda; honoraria from BeiGene, BMS, Celgene, MSD, Need Inc., Stemline and Takeda and stock options from Need Inc. RG received honoraria for advice and lectures from BristolMyers Squibb, Roche Pharma, MerckSharpDohme, Novartis, Merck-Serono, Amgen, Almirall Hermal, Pierre-Fabre, Sun Pharma, Immunocore, 4SC, Delcath, Sanofi/Regeneron. Ralf Gutzmer received travel support from SUN Pharma, Boehringer Ingelheim and PierreFabre. Ralf Gutzmer received research grants from Novartis, Sanofi/Regeneron, Merck Serono, Amgen, SUN Pharma, KyowaKirin, Admiral Hermal. RD has intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, Simcere and touchIME outside the submitted work. All remaining authors have declared no conflicts of interest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Wang, Ertl, Schmitt, Hammann, Kramer, Grabmaier, Schöberl, Anz, Piseddu, Pesch, Vera, Froehlich, Weckbach, Tomsitz, Loquai, Zimmer, Mangana, Dummer, Gutzmer, Klespe, Stege, Meiss, Thoms, Terheyden, Bröckelmann, Johnson, French and Heinzerling.)

(1) Purpose: To evaluate tumor response and survival of patients with colorectal pulmonary metastases treated by transvenous pulmonary chemoembolization (TPCE) alone with palliative intent or TPCE followed by microwave ablation (MWA) with potentially curative intent. (2) Material and methods: A total of 164 patients (64 women and 100 men; mean age: 61.8 ± 12.7 years) with unresectable colorectal lung metastases and not responding to systemic chemotherapy, who either received repetitive TPCE (Group A) or TPCE followed by MWA (Group B), were retrospectively enrolled. The revised response evaluation criteria in solid tumors were used to assess treatment response in Group A. The oncological response in Group B was divided into local tumor progression (LTP) and intrapulmonary distant recurrence (IDR) after MWA. (3) Results: The 1-, 2-, 3-, and 4-year survival rates were 70.4%, 41.4%, 22.3%, and 5%, respectively, for all patients. In Group A; the rates of stable disease; progressive disease; and partial response were at 55.4%, 41.9%, and 2.7%, respectively. The rates of LTP and IDR were 3.8%, and 63.5%, respectively, in Group B. Conclusion: TPCE is an effective treatment for colorectal lung metastases, which can be performed alone or combined with MWA.

Purpose: To evaluate the efficacy and safety of microwave ablation (MWA) as a treatment for recurrent hepatocellular carcinoma (HCC) after initial successful surgical resection., Methods: This retrospective study included 40 patients (11 women and 29 men; mean age: 62.3 ± 11.7 years) with 48 recurrent lesions of HCC after initial surgical resection that were treated by percutaneous MWA. Several parameters including complications, technical success, local tumor progression (LTP), intrahepatic distant recurrence (IDR), overall survival (OS), and progression-free survival (PFS) were evaluated in order to investigate the safety and efficacy of MWA for these recurrent HCC lesions after surgical treatment., Results: All MWA treatments were performed without complications or procedure-related deaths. Technical success was achieved in all cases. Two cases developed LTP at a rate of 5%, and IDR occurred in 23 cases at a rate of 57.5% (23/40). The 1-, 2-, 3-, 4-, and 6-year OS rates were 97%, 89.2%, 80.3%, 70.2%, and 60.2%, respectively. The 1- and 3 -year PFS rates were 50.2% and 34.6%, respectively., Conclusion: MWA is effective and safe as a local treatment for recurrent HCC after initial surgical resection.