Faculty Bibliography

Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced non-small cell lung cancer (NSCLC), yet a large proportion of patients do not respond. The lung microbiome is a key modulator of antitumor immunity, however, the functional contribution of active microbial communities and their interaction with host transcriptional programs in shaping ICI outcomes remain poorly defined. Here, we prospectively analyzed bronchoalveolar lavage (BAL) samples from 71 NSCLC patients prior to ICI initiation. We profiled the microbiome and host transcriptome in the BAL to look for microbial and host signatures in the lower airways associated with treatment response. We found that enrichment of the lower airway microbiome with oral commensals was associated with disease progression and worse prognosis of patients treated with ICI. Metatranscriptomics-derived microbial clustering revealed distinct functional profiles. The microbial cluster enriched with oral commensals, which was only present among patients with poor response to ICI, had differential regulation of pathways involved in the metabolism of short-chain fatty acids, methane, and pyruvate. This cluster also correlated with host immune pathways including upregulation of interferon signaling, neutrophil degranulation, and mitophagy, all of which could contribute to the poor response to immunotherapy. In a preclinical murine model of lung cancer with dysbiosis, inoculating lung tumor-bearing mice with oral commensals increased intratumoral neutrophils and Th17 responses and impaired ICI efficacy. Our findings support the concept that microbial communities in the lower airways influence tumor-immune interactions via defined metabolic-immune axes.

Excessive cyclin D1 accumulation is a frequent oncogenic event in head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC). Although classically associated with enhanced proliferation and genomic instability, we revealed that cyclin D1 dysregulation induces metabolic rewiring that leads to unexpected metabolic dependencies. Sustained nuclear retention of cyclin D1 drove metabolic reprogramming through activation of CDK4/6 and downregulation of mitochondrial isocitrate dehydrogenase 3 (IDH3), reducing α-ketoglutarate and NADH production. This metabolic alteration increased glutamine dependence and elevated autophagic flux, and co-targeting autophagy and glutamine metabolism suppressed the growth of squamous cell carcinoma models in vitro and in vivo. Together, these findings highlight a therapeutic strategy for HNSCC and ESCC that leverages metabolic reprogramming induced by dysregulated cyclin D1/CDK4 activity, with potential applicability to patients with tumors refractory to conventional therapies.

Pancreatic ductal adenocarcinoma (PDAC) is refractory to most therapies, including immunotherapies, for which reinvigoration of CD8 T cells through immune checkpoint blockade is insufficient to induce long-term, durable remissions. Direct KRAS inhibitors (KRASi) have shown clinical promise, although acquired resistance is common. We modeled KRASi response and relapse in mice and demonstrated that, unlike chemotherapy or combinations with checkpoint blockade, an interleukin (IL)-21 cytokine mimic (21h10) induced long-term, durable remissions. Its efficacy depends on T helper 1 (Th1)-polarized CD4 T cells, but not on CD8 T cells or tumor cell expression of major histocompatibility complex class I (MHC class I). Specifically, CD4 T cells primed by type 2 conventional dendritic cells (cDC2s) produce interferon γ (IFN-γ), which promotes macrophage-mediated phagocytosis of tumor cells. Ex vivo treatment of human PDAC specimens with 21h10 induces IFN-γ production by infiltrating T cells. Thus, IL-21-elicited CD4 T cells exert antitumor activity in mice and potentially in humans, converting transient responses to KRAS inhibition into durable remissions.

Histone lysine methylation, primarily mediated by the enhancer methyltransferase KMT2D (MLL4), regulates gene expression through H3K4 mono- and di-methylation. Dysregulation of KMT2D disrupts enhancer activation and contributes to tumorigenesis and cellular plasticity across multiple cancers, including lung, prostate, bladder, head and neck, and pancreatic tumors. KMT2D functions in a context-dependent manner, acting as either a tumor suppressor or oncogenic driver, and modulates key phenotypic transitions-such as epithelial-to-mesenchymal, squamous, endothelial, and neuroendocrine states-that underlie metastasis and therapeutic resistance. Beyond its tumor-intrinsic roles, KMT2D loss remodels the tumor immune microenvironment by enhancing antigen presentation and effector T-cell infiltration, thereby sensitizing tumors to immune checkpoint blockade. Understanding how KMT2D interfaces with signaling pathways such as PI3K/AKT, TGF-β, and NOTCH to regulate plasticity and immunogenicity will be critical for leveraging its biomarker and therapeutic potential. This review summarizes current insights into KMT2D's roles in cancer progression, lineage plasticity, therapy resistance, and immune regulation, highlighting its emerging relevance in precision oncology.

Sickness behaviors are common in cancer-associated cachexia and affect up to half of lung cancer patients. We demonstrate that among the most common cancer mutations, loss of liver kinase B1 (Lkb1) promotes the development of cachexia in preclinical models of lung cancer. In an effort to improve caloric intake with an obesogenic high-fat diet, we paradoxically observed worsened cachexia-associated sickness. We found that local production of prostaglandin E2 (PGE₂), rather than circulating factors, promotes sickness and that genetic, dietary, and pharmacological inhibition of tumor-derived PGE₂ suppresses sickness and cachexia. Notably, we demonstrate that lung sensory neuron abrogation prevents PGE₂-dependent cachexia. Our study establishes localized tumor-derived signals to sensory neurons, rather than circulating factors, as drivers of cachexia and highlights a previously unknown role of the peripheral nervous system in cancer cachexia.

Pancreatic ductal adenocarcinoma (PDAC) relies on elevated autophagy to support metabolism, proliferation, and immune evasion. Inhibiting autophagy has been reported to improve response rates in patients with PDAC. In this work, we identified a mechanism to explain how loss of autophagy in PDAC triggers reprogramming of the tumor microenvironment (TME) to ultimately stimulate an antitumor response. Autophagy inhibition in PDAC recruited macrophages via the CXCL1/2-CXCR2 axis. Simultaneously, loss of autophagy resulted in a decrease of the canonical "don't eat me" ligand CD47 on tumor cells, thereby inducing their susceptibility to macrophage phagocytosis. While CD8+ T cells were critical to the anti-tumor immune response to autophagy inhibition in PDAC, they were not directly involved in cytotoxicity but played a critical role in stimulating macrophage phagocytosis of tumor cells. Taken together, this study strongly supports the implementation of autophagy inhibition in pancreatic cancer and highlights a crucial link between PDAC biology and the TME-macrophage crosstalk that effectively promotes tumor cell killing.

Advances in targeted therapies, immunotherapy, and early detection have revolutionized lung cancer treatment and extended survival. Nonetheless, lung cancer remains highly fatal. Here, we identify knowledge gaps and propose critical areas of future research, aligning with the mission of the AACR Lung Cancer Task Force. We delineate research priorities, including advancing prevention initiatives, enhancing early detection strategies, developing novel treatments, and refining patient stratification. Addressing disparities and increasing efforts on relatively neglected lung cancer subtypes are also essential. Finally, international collaboration, centralized clinical trial databases, novel clinical trial designs, and artificial intelligence-driven analytics should accelerate precision medicine and aid in elucidating drug resistance mechanisms. Together, these efforts promise to improve patient outcomes.

Breast cancer remains the second leading cause of cancer-related mortality among women, with triple-negative breast cancer (TNBC) exhibiting a particularly poor five-year prognosis. Here, we demonstrated that, among genetic and pharmacological perturbations targeting DNA replication, suppression of DNA polymerase epsilon (POLE) induced a potent, TNBC-specific gene expression signature enriched in inflammatory cytokines that are transcriptional targets of NF-κB. TNBC cells exhibited markedly higher levels of DNA damage and canonical NF-κB activation compared to luminal breast cancer cells. Notably, NF-κB activation in this context depended on the canonical component RELA but not the non-canonical component RELB. Mechanistically, ATM, STING, and RIG-I each contributed to NF-κB activation following POLE suppression. POLE suppression in an in vivo murine TNBC model led to cancer cell-intrinsic elimination of tumor burden and increased immune cell infiltration. Together, these findings support a model in which replication stress from POLE inhibition triggers robust NF-κB-mediated inflammation and immune microenvironment remodeling in TNBC and can independently trigger tumor eradication. These results suggest a potential therapeutic avenue for targeting POLE in TNBC.

UNLABELLED:LKB1 mutations in lung cancer promote an immunosuppressive tumor microenvironment, but the underlying mechanisms remain unknown. Using genetically engineered mouse models and human tumor samples, we demonstrate that LKB1 loss leads to high expression of the cytokine leukemia-inhibitory factor (LIF), which through a cancer cell-autonomous autocrine loop, orchestrates the infiltration of immunosuppressive SiglecFHi neutrophils and Arg1+ interstitial macrophages. Genetic deletion of Lifr, the receptor for LIF, on Lkb1-mutant lung tumors revealed that autocrine LIF signaling induces tumor plasticity and the emergence of a Sox17+ dedifferentiated inflammatory cell state. Antibody-mediated LIF neutralization selectively eliminates the Sox17+ tumor cell state, reduces immunosuppressive myeloid cells, and enhances antitumor T-cell responses. Our study uncovers a novel LKB1-LIF axis driving immune evasion and identifies LIF as a potential therapeutic target in LKB1-mutant lung cancer. This work highlights the interplay between tumor genetics, cellular plasticity, and immune regulation in lung cancer progression. SIGNIFICANCE/UNASSIGNED:LKB1-mutant lung cancers express LIF, which induces an immunosuppressive Sox17+ tumor state. Anti-LIF therapy eliminates this state and restores antitumor immunity, revealing a novel vulnerability in this aggressive cancer subtype lacking effective targeted therapies.

Aneuploidy is common in cancer and has been implicated in promoting tumor progression, yet the underlying mechanisms remain poorly understood. By generating models of aneuploidy, we found that aneuploidy confers resistance to reactive oxygen species (ROS)-mediated cell death, independent of the specific chromosomes gained or lost. Mechanistically, poly(ADP-ribose) polymerase 1 (PARP1) is suppressed in aneuploid cells, which inhibits PARP1-mediated cell death (parthanatos). We validated aneuploidy-associated PARP1 suppression across 15 cell models and human tumors, with pronounced effects in metastatic tumors. Importantly, PARP1 downregulation promotes tumor metastasis while PARP1 upregulation suppresses it. Through a genome-wide CRISPR screen and functional validation, we identified the transcription factor CCAAT/enhancer-binding protein beta (CEBPB) as a mediator of PARP1 downregulation and ROS resistance in aneuploid cells. Lysosomal dysfunction serves as the upstream activator of CEBPB in aneuploid cells. We propose that aneuploidy-driven CEBPB activation suppresses PARP1, fostering ROS resistance and cancer progression.