CRACD loss promotes small cell lung cancer tumorigenesis via EZH2-mediated immune evasion.

The mechanisms underlying immune evasion and immunotherapy resistance in small cell lung cancer (SCLC) remain unclear. Herein, we investigate the role of CRACD tumor suppressor in SCLC. We found that CRACD is frequently inactivated in SCLC, and Cracd knockout (KO) significantly accelerates SCLC development driven by loss of Rb1, Trp53, and Rbl2. Notably, the Cracd-deficient SCLC tumors display CD8+ T cell depletion and suppression of antigen presentation pathway. Mechanistically, CRACD loss silences the MHC-I pathway through EZH2. EZH2 blockade is sufficient to restore the MHC-I pathway and inhibit CRACD loss-associated SCLC tumorigenesis. Unsupervised single-cell transcriptomic analysis identifies SCLC patient tumors with concomitant inactivation of CRACD, impairment of tumor antigen presentation, and downregulation of EZH2 target genes. Our findings define CRACD loss as a new molecular signature associated with immune evasion of SCLC cells and proposed EZH2 blockade as a viable option for CRACD-negative SCLC treatment.

Effect of chromatin modifiers on the plasticity and immunogenicity of small-cell lung cancer.

Tumor suppressor genes (TSGs) are often involved in maintaining homeostasis. Loss of tumor suppressor functions causes cellular plasticity that drives numerous types of cancer, including small-cell lung cancer (SCLC), an aggressive type of lung cancer. SCLC is largely driven by numerous loss-of-function mutations in TSGs, often in those encoding chromatin modifiers. These mutations present a therapeutic challenge because they are not directly actionable. Alternatively, understanding the resulting molecular changes may provide insight into tumor intervention strategies. We hypothesize that despite the heterogeneous genomic landscape in SCLC, the impacts of mutations in patient tumors are related to a few important pathways causing malignancy. Specifically, alterations in chromatin modifiers result in transcriptional dysregulation, driving mutant cells toward a highly plastic state that renders them immune evasive and highly metastatic. This review will highlight studies in which imbalance of chromatin modifiers with opposing functions led to loss of immune recognition markers, effectively masking tumor cells from the immune system. This review also discusses the role of chromatin modifiers in maintaining neuroendocrine characteristics and the role of aberrant transcriptional control in promoting epithelial-to-mesenchymal transition during tumor development and progression. While these pathways are thought to be disparate, we highlight that the pathways often share molecular drivers and mediators. Understanding the relationships among frequently altered chromatin modifiers will provide valuable insights into the molecular mechanisms of SCLC development and progression and therefore may reveal preventive and therapeutic vulnerabilities of SCLC and other cancers with similar mutations.

T-bet+ Memory B Cells Link to Local Cross-Reactive IgG upon Human Rhinovirus Infection.

Human rhinoviruses cause the common cold and exacerbate chronic respiratory diseases. Although infection elicits neutralizing antibodies, these do not persist or cross-protect across multiple rhinovirus strains. To analyze rhinovirus-specific B cell responses in humans, we developed techniques using intact RV-A16 and RV-A39 for high-throughput high-dimensional single-cell analysis, with parallel assessment of antibody isotypes in an experimental infection model. Our approach identified T-bet+ B cells binding both viruses that account for ∼5% of CXCR5- memory B cells. These B cells infiltrate nasal tissue and expand in the blood after infection. Their rapid secretion of heterotypic immunoglobulin G (IgG) in vitro, but not IgA, matches the nasal antibody profile post-infection. By contrast, CXCR5+ memory B cells binding a single virus are clonally distinct, absent in nasal tissue, and secrete homotypic IgG and IgA, mirroring the systemic response. Temporal and spatial functions of dichotomous memory B cells might explain the ability to resolve infection while rendering the host susceptible to re-infection.