African Ancestry Influences the Breast Tumor Immune Microenvironment in TNBC
The incidence and mortality of triple-negative breast cancer (TNBC) are significantly higher in women of sub-Saharan African descent, with previous evaluations of racial differences being heavily reliant on self-reported race in U.S. populations. Martini and colleagues performed RNA sequencing of an international cohort of African Americans and West and East Africans, resulting in the identification of 613 genes associated with African ancestry and >2,000 genes connected to regional African ancestry. Differences in normal breast tissue were observed in a portion of African-associated genes, and distinct immunologic patterns in patients of African descent were detected. Together, these results may explain differential clinical outcomes between race groups.
Somatic Differences Correlate with Genetic Ancestry in a Pan-Cancer Cohort
Genetic ancestry is an important biological determinant of cancer health disparities. Arora and colleagues show that, although typically inferred using genome-wide markers, genetic ancestry can be reliably inferred from clinical cancer gene panel sequencing data, in which a pan-cancer cohort of 45,157 patients was analyzed, and differences in the frequency and clinical actionability of somatic alterations for different ancestral groups were characterized. The large cohort size enabled the identification of known and novel ancestry-specific associations and highlighted lower rates of clinically actionable mutations in patients of African ancestry as compared to European ancestry.
Developmental Profiling Classifies Cancers of Unknown Primary
While some cancers may show reactivation of early developmental programs, a systematic catalog of how tumors relate to these developmental programs is lacking. Comparing transcriptomes from over 10,000 tumors to a single-cell atlas of embryogenesis, Moiso and colleagues recorded each tumor's developmental profile. Distinct profiles allowed the construction of a machine learning classifier that used each tumor's developmental profile to determine its classification. The application of the classifier to cancers of unknown primary revealed predictions for each case, suggesting developmental profiling could be an effective classification scheme for cancers of unknown primary.
Proteogenomic Analysis Reveals Markers of Chemotherapy Resistance in TNBC
To identify biological features associated with chemotherapy response in triple-negative breast cancer (TNBC), Anurag, Jaehnig, Krug, Lei, and colleagues deployed proteogenomic approaches and showed that chemotherapy sensitivity was marked by elevated cell cycle–, interferon-gamma response–, and immune-related pathways, while resistance was marked by upregulated metabolic pathways. Resistance-associated genomic deletion spanning cytoband 19q13.31–33 harboring DNA Ligase 1 (LIG1) was also identified, with LIG1 loss being associated with lack of response and poor prognosis in patients with TNBC. LIG1 loss also correlated with higher chromosomal instability and poor prognosis in other cancer types, highlighting that LIG1 loss has broad clinical significance.
T cell–Excluding CAF Subsets Were Identified in Non–Small Cell Lung Carcinoma
T-cell exclusion from the tumor bed correlates with poor response to immune checkpoint blockade, yet the cellular and molecular mechanisms underlying T-cell marginalization in solid tumors are poorly understood. Grout and colleagues paired molecular and spatial analyses to study how fibroblasts contribute to T-cell localization in the tumor microenvironment in human non–small cell lung carcinoma and identified populations of cancer-associated fibroblasts (CAF) that form specific patterns of dense and aligned fibers around tumor nests that are associated with CD3+ and CD8+ T-cell exclusion. Importantly, this study characterizes intratumor organization, revealing molecular factors behind intertumor CAF and T-cell heterogeneity.
Tumor-Infiltrating B and Plasma Cells Play a Role in Lung Cancer Immunopathology
The landscape of tumor-infiltrating B and plasma cells (TIB) in lung cancer is poorly understood. Hao, Han, Sinjab, and colleagues built a large single-cell atlas of TIBs in early-stage lung adenocarcinoma (LUAD) using comprehensive single-cell and spatial analyses of 16 LUADs and 47 normal tissues with differing distances from tumors. Twelve TIB subsets were identified, with some demonstrating extensive remodeling. TIBs markedly differed by smoking, stage, as well as driver mutations and were closely coupled with immunotherapy response. This study reveals unappreciated roles for TIBs in LUAD immunopathology and outcomes and provides a valuable resource to identify new targets for immune-based therapy.
NT5C2 Inhibition Reverses 6-MP Resistance in Acute Lymphoblastic Leukemia
Activating NT5C2 mutations confer resistance to 6-mercaptopurine (6-MP) in relapsed acute lymphoblastic leukemia (ALL). Reglero, Dieck, and colleagues developed CRCD2, a small-molecule NT5C2 inhibitor effective in reversing 6-MP resistance in leukemias bearing relapse-associated mutant forms of NT5C2. CRCD2 also increased the sensitivity of NT5C2 wild-type leukemias to 6-MP, with NT5C2 Ser502 phosphorylation being described as a nongenetic mechanism interfering with 6-MP efficacy in ALL. The study provides novel insight into the mechanisms of resistance in ALL and establishes a basis for the development of clinically active NT5C2 inhibitors to overcome 6-MP resistance in this disease.
Kinase Inhibitors Mobilize Pharmacologically Targetable Endogenous Mutators
EGFR-specific tyrosine kinase inhibitors (EGFRi), especially osimertinib, have changed lung cancer therapy, but secondary on-target mutations and additional adaptations confer drug resistance. Noronha and colleagues demonstrated that, similar to bacteria that can activate a variety of mutation-prone processes (the SOS response) after antibiotic treatment, EGFRi-treated lung cancer upregulates GAS6, which acts as a sensor of apoptosis and activates a receptor tyrosine kinase, AXL. Once stimulated, AXL mobilizes low-fidelity mechanisms of DNA replication, which generate mutations and subsequent drug tolerance. Blocking this process, specifically AXL, can prevent the emergence of osimertinib resistance in xenograft models, suggesting these findings can offer new treatment strategies.
Small-Molecule Inhibition of ENL Is a Therapeutic Strategy against AML
The chromatin reader ENL has been identified as a critical dependency in acute myeloid leukemia (AML), but its therapeutic potential remains unclear. Liu and colleagues developed a potent, on-target, and orally bioavailable small-molecule inhibitor of ENL: TDI-11055. Treatment with TDI-11055 displaces ENL from chromatin by blocking its YEATS domain interaction with acylated histones, leading to suppression of oncogenic gene expression programs and induction of cell differentiation in MLL-rearranged and NPM1-mutated leukemia. Furthermore, in vivo treatment with TDI-11055 blocks disease progression in these AML subsets without causing overt toxicity. This work reveals displacement of ENL from chromatin as a promising therapeutic strategy for AML.