Blood
Serum Free Light Chains in a Racially Diverse Population Including African Americans and Populations from South Africa
Bertamini L, Alberge JB, Lee DJ, El-Khoury H, Kim S, Fleming G, Murphy C, Colchie J, Davis MI, Perry J, Lightbody ED, Allam S, Getz G, Karlson EW, Munshi N, Anderson KC, Trippa L, Marinac CR, Ghobrial IM
Detection of light chain (LC) monoclonal gammopathies (MGs) traditionally relies on serum free LC (FLC) ?, ?, and their ratio (?/?) reference ranges based on a mostly White population. We investigated FLC values in a racially diverse population by screening 10?035 individuals for heavy chain MG, identifying 9028 negative cases whose FLC were measured. Participants included 4149 from the PROMISE study (United States, n = 2383; South Africa, n = 1766) and 4879 from the Mass General Brigham Biobank, with 44% self-identifying as Black. Using standard FLC reference ranges, 1074 of 10?035 individuals (10.7%) were diagnosed with LC monoclonal gammopathy of undetermined significance (MGUS), with 99% being ?-restricted. In the United States, 14.8% of Black and 4% of White individuals were diagnosed (P < .01). Among US participants of African (AFR) and European (EUR) genetic ancestry, 14.4% AFR and 2.9% EUR were diagnosed (P < .01). Among South Africans (100% Black), 27.8% were diagnosed using standard ranges. To avoid overdiagnosis, we propose a new ?/? ratio reference range (0.686 to 2.10) for populations of AFR descent with normal renal function, with standard values for ? and ? being 7.97 to 77.50 mg/L and 6.20 to 49.20 mg/L, respectively. This reduces LC-MGUS overdiagnosis by 91% (10.7% vs 0.97%). Using the new reference, LC-MGUS accounts for 8.8% of MGUS cases, with 74% being ?-restricted, consistent with LC myeloma rates. These findings highlight the importance of basing disease definitions, such as MGUS, on diverse populations. Adopting our proposed FLC reference values would reduce MGUS overdiagnosis among Black individuals, avoiding unnecessary financial, psychological, and medical consequences. This study includes data from NCT03689595.
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Cell
HIF Regulates Multiple Translated Endogenous Retroviruses: Implications for Cancer Immunotherapy
Jiang Q, Braun DA, Clauser KR, Ramesh V, Shirole NH, Duke-Cohan JE, Kramer NJ, Forman C, Lippincott IE, Klaeger S, Phulphagar KM, Chea V, Kim N, Vanasse AP, Saad E, Carulli I, Pinjusic K, Jiang Y, Li R, Syamala S, Rachimi S, Verzani EK, Stevens JD, Lane WJ, Camp SY, Meli K, Herbert ZT, Qiu X, Cejas P, Long HW, Van Allen EM, Choueiri TK, Churchman LS, Abelin JG, Gurer C, MacBeath G, Carr SA, Keskin DB, Wu CJ, Kaelin WG Jr
Clear cell renal cell carcinoma (ccRCC), despite having a low mutational burden, is considered immunogenic because it occasionally undergoes spontaneous regressions and often responds to immunotherapies. The signature lesion in ccRCC is inactivation of the VHL tumor suppressor gene and consequent upregulation of the HIF transcription factor. An earlier case report described a ccRCC patient who was cured by an allogeneic stem cell transplant and later found to have donor-derived T cells that recognized a ccRCC-specific peptide encoded by a HIF-responsive endogenous retrovirus (ERV), ERVE-4. We report that ERVE-4 is one of many ERVs that are induced by HIF, translated into HLA-bound peptides in ccRCCs, and capable of generating antigen-specific T cell responses. Moreover, ERV expression can be induced in non-ccRCC tumors with clinical-grade HIF stabilizers. These findings have implications for leveraging ERVs for cancer immunotherapy.
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Cell
Lysine Vitcylation is a Vitamin C-Derived Protein Modification that Enhances STAT1-Mediated Immune Response
He X, Wang Q, Cheng X, Wang W, Li Y, Nan Y, Xiu B, Jiang T, Bergholz JS, Gu H, Chen F, Xie S, Wei Y, Lee J, Asara JM, Cantley LC, Zhao JJ
Vitamin C (vitC) is essential for health and shows promise in treating diseases like cancer, yet its mechanisms remain elusive. Here, we report that vitC directly modifies lysine residues to form "vitcyl-lysine"-a process termed vitcylation. Vitcylation occurs in a dose-, pH-, and sequence-dependent manner in both cell-free systems and living cells. Mechanistically, vitC vitcylates signal transducer and activator of transcription-1 (STAT1)- lysine-298 (K298), impairing its interaction with T cell protein-tyrosine phosphatase (TCPTP) and preventing STAT1-Y701 dephosphorylation. This leads to enhanced STAT1-mediated interferon (IFN) signaling in tumor cells, increased major histocompatibility complex (MHC)/human leukocyte antigen (HLA) class I expression, and activation of anti-tumor immunity in vitro and in vivo. The discovery of vitcylation as a distinctive post-translational modification provides significant insights into vitC's cellular function and therapeutic potential, opening avenues for understanding its biological effects and applications in disease treatment.
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Nature
Programs, Origins and Immunomodulatory Functions of Myeloid Cells in Glioma
Miller TE, El Farran CA, Couturier CP, Chen Z, D'Antonio JP, Verga J, Villanueva MA, Gonzalez Castro LN, Tong YE, Chiocca AN, Zhang Y, Fischer DS, Guerriero JL, Suva ML, Shalek AK, Bernstein BE
Gliomas are incurable malignancies notable for having an immunosuppressive microenvironment with abundant myeloid cells, the immunomodulatory phenotypes of which remain poorly defined1. Here we systematically investigate these phenotypes by integrating single-cell RNA sequencing, chromatin accessibility, spatial transcriptomics and glioma organoid explant systems. We discovered four immunomodulatory expression programs: microglial inflammatory and scavenger immunosuppressive programs, which are both unique to primary brain tumours, and systemic inflammatory and complement immunosuppressive programs, which are also expressed by non-brain tumours. The programs are not contingent on myeloid cell type, developmental origin or tumour mutational state, but instead are driven by microenvironmental cues, including tumour hypoxia, interleukin-1?, TGF? and standard-of-care dexamethasone treatment. Their relative expression can predict immunotherapy response and overall survival. By associating the respective programs with mediating genomic elements, transcription factors and signalling pathways, we uncover strategies for manipulating myeloid-cell phenotypes. Our study provides a framework to understand immunomodulation by myeloid cells in glioma and a foundation for the development of more-effective immunotherapies.
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Nature Communications
CHAMP1 Complex Directs Heterochromatin Assembly and Promotes Homology-Directed DNA Repair
Li F, Syed A, Elbakry A, Holmer N, Nguyen H, Mukkavalli S, D'Andrea AD
The CHAMP1 complex, a little-known but highly conserved protein complex consisting of CHAMP1, POGZ, and HP1?, is enriched in heterochromatin though its cellular function in these regions of the genome remain unknown. Here we show that the CHAMP complex promotes heterochromatin assembly at multiple chromosomal sites, including centromeres and telomeres, and promotes homology-directed repair (HDR) of DNA double strand breaks (DSBs) in these regions. The CHAMP1 complex is also required for heterochromatin assembly and DSB repair in highly-specialized chromosomal regions, such as the highly-compacted telomeres of ALT (Alternative Lengthening of Telomeres) positive tumor cells. Moreover, the CHAMP1 complex binds and recruits the writer methyltransferase SETDB1 to heterochromatin regions of the genome and is required for efficient DSB repair at these sites. Importantly, peripheral blood lymphocytes from individuals with CHAMP1 syndrome, an inherited neurologic disorder resulting from heterozygous mutations in CHAMP1, also exhibit defective heterochromatin clustering and defective repair of DSBs, suggesting that a defect in DNA repair underlies this syndrome. Taken together, the CHAMP1 complex has a specific role in heterochromatin assembly and the enhancement of HDR in heterochromatin.
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Nature Communications
Explainable Artificial Intelligence of DNA Methylation-Based Brain Tumor Diagnostics
Benfatto S, Hovestadt V
We have recently developed a machine learning classifier that enables fast, accurate, and affordable classification of brain tumors based on genome-wide DNA methylation profiles that is widely employed in the clinic. Neuro-oncology research would benefit greatly from understanding the underlying artificial intelligence decision process, which currently remains unclear. Here, we describe an interpretable framework to explain the classifier's decisions. We show that functional genomic regions of various sizes are predominantly employed to distinguish between different tumor classes, ranging from enhancers and CpG islands to large-scale heterochromatic domains. We detect a high degree of genomic redundancy, with many genes distinguishing individual tumor classes, explaining the robustness of the classifier and revealing potential targets for further therapeutic investigation. We anticipate that our resource will build up trust in machine learning in clinical settings, foster biomarker discovery and development of compact point-of-care assays, and enable further epigenome research of brain tumors. Our interpretable framework is accessible to the research community via an interactive web application (https://hovestadtlab.shinyapps.io/shinyMNP/).
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New England Journal of Medicine
Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia
Brown JR
BACKGROUND: Whether fixed-duration acalabrutinib-venetoclax (with or without obinutuzumab) would result in better progression-free survival than chemoimmunotherapy in patients with untreated chronic lymphocytic leukemia (CLL) is unknown.
METHODS: In this phase 3, open-label trial, we included patients 18 years of age or older who had an Eastern Cooperative Oncology Group performance-status score of 0 to 2 (range, 0 to 5, with higher numbers indicating greater disability) and who did not have a 17p deletion or TP53 mutation. Patients were randomly assigned, in a 1:1:1 ratio, to receive acalabrutinib-venetoclax (acalabrutinib, cycles 1 to 14; venetoclax, cycles 3 to 14), acalabrutinib-venetoclax-obinutuzumab (as above, plus obinutuzumab, cycles 2 to 7), or chemoimmunotherapy with the investigator's choice of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab (cycles 1 to 6). The primary end point was progression-free survival (acalabrutinib-venetoclax vs. chemoimmunotherapy) in the intention-to-treat population, assessed by blinded independent central review.
RESULTS: A total of 867 patients underwent randomization: 291 were assigned to receive acalabrutinib-venetoclax, 286 acalabrutinib-venetoclax-obinutuzumab, and 290 chemoimmunotherapy (of whom 143 received fludarabine-cyclophosphamide-rituximab and 147 bendamustine-rituximab). The median age of the patients was 61 years (range, 26 to 86), 64.5% were men, and 58.6% had unmutated IGHV. Estimated 36-month progression-free survival at a median follow-up of 40.8 months was 76.5% with acalabrutinib-venetoclax, 83.1% with acalabrutinib-venetoclax-obinutuzumab, and 66.5% with chemoimmunotherapy (hazard ratio for disease progression or death with acalabrutinib-venetoclax vs. chemoimmunotherapy, 0.65 [95% confidence interval {CI}, 0.49 to 0.87], P?=?0.004; for the comparison of acalabrutinib-venetoclax-obinutuzumab with chemoimmunotherapy, P<0.001). Estimated 36-month overall survival was 94.1% with acalabrutinib-venetoclax, 87.7% with acalabrutinib-venetoclax-obinutuzumab, and 85.9% with chemoimmunotherapy. Neutropenia, the most common adverse event of clinical interest of grade 3 or higher, was reported in 32.3%, 46.1%, and 43.2% in the three groups, respectively; death from coronavirus disease 2019 was reported in 10, 25, and 21 patients in the three groups.
CONCLUSIONS: Acalabrutinib-venetoclax with or without obinutuzumab significantly prolonged progression-free survival as compared with chemoimmunotherapy in fit patients with previously untreated CLL. (Funded by AstraZeneca; AMPLIFY ClinicalTrials.gov number, NCT03836261.).
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New England Journal of Medicine
Resilience and the Fallacy of "One Size Fits All"
Rosenberg AR
As a pediatric palliative care physician, I often ask people a simple question: “How are you handling this experience of illness?” Over the years, I have heard myriad responses. People talk about their family, their church community, or the support of a trusted clinician–advocate. They talk about grit, humor, optimism, or their practice of taking it day by day or of planning ahead. They talk about exercising, reading good books, and distracting themselves with work, social media, and chores. They talk about faith, hope, and their identity as a caregiver, partner, daughter, son, or friend. In short, people respond by describing their own resilience.
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Annals of Surgical Oncology
Gait Speed as a Measure of Frailty and Outcomes After Lung Resection
Singh A, Xie Y, Mazzola E, Wang S, McAllister M, Pezeshkian F, Frain LN, Wilder FG, Steimer D, Jaklitsch MT, DuMontier C
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Clinical Cancer Research
Duvelisib with Docetaxel for Patients with Anti-PD-1 Refractory, Recurrent, or Metastatic Head and Neck Squamous Cell Carcinoma
Hanna GJ, Oakley LB, Shi R, ONeill A, Shin KY, Scarfo N, Sehgal K, Dennis MJ, Quinn N, Jo VY, Wong K, Haddad RI
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Journal for ImmunoTherapy of Cancer
Phase I Study of Ribociclib (CDK4/6 Inhibitor) with Spartalizumab (PD-1 Inhibitor) with and without Fulvestrant in Metastatic Hormone Receptor-Positive Breast Cancer or Advanced Ovarian Cancer
Garrido-Castro AC, Graham N, Ali LR, Herold C, Desrosiers J, Do K, Parsons H, Li T, Goel S, DiLullo M, Wrabel E, Liu JF, Mittendorf EA, Dougan SK, Tayob N, Shapiro GI, Tolaney SM
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PLoS Computational Biology
Tumor-Immune Partitioning and Clustering Algorithm for Identifying Tumor-Immune Cell Spatial Interaction Signatures within the Tumor Microenvironment
Lau MC, Väyrynen JP, Haruki K, Zhao M, Dias Costa A, Gu S, da Silva A, Ugai T, Arima K, Takashima Y, Hamada T, Wu CJ, Meyerhardt JA, Ogino S, Nowak JA
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Science Translational Medicine
A Window-of-Opportunity Trial Reveals Mechanisms of Response and Resistance to Navtemadlin in Patients with Recurrent Glioblastoma
Rendo V, Lee EQ, Bossi C, Khuu N, Pal S, Azazmeh N, Rashid R, Lin JR, Cusick M, Reynolds ARN, Fassinou ACR, Ayoub G, Malinowski S, Lapinskas E, Pisano W, Jeang J, Stopka SA, Regan MS, Pelton K, Huang RY, Sarosiek KA, Sorger PK, Santagata S, Agar NYR, Alexander BM, Wen PY, Ligon KL, Beroukhim R
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