About

Steven M. Dubinett is a distinguished professor and a key figure in the Department of Pharmacology at the University of California, Los Angeles. His research interests focus on the immune suppression in lung cancer, particularly the role of inflammation and immunity in the pathogenesis of pulmonary premalignancy. His work aims to improve early detection and cancer interception, and he conducts mechanism-based translational and clinical studies to evaluate combination immunotherapies for advanced non-small cell lung cancer. Dubinett's research program has been funded by notable organizations including Stand Up to Cancer, the NCI Moonshot Human Tumor Atlas Network, NCI Early Detection Research Network, NCI Molecular Characterization Laboratory Program, and CIRM. His background includes initial research at Massachusetts General Hospital, where he participated in the first clinical trial using tumor-infiltrating lymphocytes to treat cancer patients, observing significant responses in renal cancer and melanoma but not in lung cancer. Since joining UCLA in 1988, he has dedicated his career to understanding why lung cancer patients do not respond to immunotherapy, leading to significant contributions in the field of lung cancer immunology.

Research topics

• Medicine
• Internal medicine
• Pathology
• Gastroenterology
• Virology
• Oncology
• Immunology

Selected publications

• In vivo imaging of mitochondrial membrane potential in non-small-cell lung cancer

  UNC Libraries · 2025-06-28

  articleOpen access
  PublisherDOI

• Supplementary Figure S4 from Characteristics of a <i>CCL21</i> Gene–Modified Dendritic Cell Vaccine Utilized for a Clinical Trial in Non–Small Cell Lung Cancer

  2025-02-04

  preprintOpen access

  <p>Supplementary Figure S4. Quality control measures of single cell RNA-sequencing analysis.</p>

  PublisherDOI

• Abstract 759: Spatial transcriptomics identifies unique tumor and microenvironment pathomic programs that are associated with the lung premalignancy and adenocarcinoma continuum

  Cancer Research · 2025-04-21 · 1 citations

  article

  Abstract Background: Lung adenocarcinoma (LUAD) is one of the most prevalent and lethal cancer types worldwide. However, our understanding of the transition from normal-appearing tissue (NAT) to adenomatous lung premalignant lesions (aPMLs) and LUADs, particularly within a spatial context, remains limited. This study aims to address this gap by systemically analyzing the pathologic continuum of NAT > aPML > LUAD using spatial transcriptomics (ST). Methods: High-resolution spatial profiling was conducted on 56 samples from 25 patients with paired aPMLs and LUADs using the Visium ST platform. Non-negative matrix factorization was conducted to identify transcriptional programs for each sample, following clustering analysis to define consensus metaprograms across the cohort. Additionally, spatial molecular imaging was performed on an expanded cohort of 188 cores arranged into eight tissue microarrays using the Xenium in situ platform with a customized lung cancer gene panel to establish a single-cell spatial atlas of the disease continuum and systemically investigate spatial organization, cellular neighborhoods and interactions. Results: Eight distinct metaprograms (MP1∼8) were identified, distinguishing stromal (MP2), myeloid (MP4), lymphoid (MP6), and epithelial (MP3, MP5) compartments. Additionally, metaprograms were identified for the lung capillary bed (MP7), stressed cellular state (MP8), and mosaic cellular patterns (MP1). These metaprograms correlated strongly with pathological annotations and captured fine tissue structures like lymphoid aggregates. LUADs and aPMLs showed distinct MP profiles, with MP3 and MP6 being highly abundant in LUADs, while MP1, MP4, MP5 and MP7 were more abundant in aPMLs. Specifically, we observed positive correlations between MP3 and MP6, as well as between MP4 and MP5 in sample distributions, indicating co-evolution of tumor and immune microenvironments during disease progression. Xenium data complemented these findings by revealing distinct compositions of microenvironmental cellular states and tumor neighborhood structures across aPML and LUAD lesions. A total of 44 cell states were defined. Specifically, NK cells were depleted in aPMLs and LUADs compared with NAT, accompanied by an enrichment of regulatory T cells and myofibroblastic cancer-associated fibroblasts (CAFs) in the latter. Additionally, pro-inflammatory cellular subsets, including IL1B+ macrophages and IL6+ inflammatory CAFs were more abundant in tumor neighborhoods of aPMLs compared to LUADs, potentially contributing to the pre-malignant to malignant transition. Conclusions: This study offers a comprehensive molecular and cellular landscape of aPML and LUAD, laying a crucial foundation for future mechanistic studies aimed at early disease interception. Citation Format: Yibo Dai, Fuduan Peng, Ansam Sinjab, Sujuan Yang, Minyue Chen, Warapen Treekitkarnmongkol, Lorena I. Gomez Bolanos, Tieling Zhou, Alejandra G. Serrano, Jianlong Liao, Guangsheng Pei, Yunhe Liu, Yang Liu, Jiahui Jiang, Kyung Serk Cho, Yanshuo Chu, Kai Yu, Ruiping Wang, Jiping Feng, Zahraa Rahal, Guangchun Han, Naoe Jimbo, Takuo Hayashi, Satsuki Kishikawa, Kazuya Takamochi, Akshay Basi, Avrum Spira, Steven Dubinett, Tomokazu Itoh, Takashi Yao, Kenji Suzuki, Luisa M. Solis, Stephen Swisher, Mingyao Li, Junya Fujimoto, Ignacio I. Wistuba, Jared Burks, Kadir Akdemir, Hind Refai, Katy Rezvani, Jeffrey Myers, Humam Kadara, Linghua Wang. Spatial transcriptomics identifies unique tumor and microenvironment pathomic programs that are associated with the lung premalignancy and adenocarcinoma continuum [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 759.

  PublisherDOI

• Supplementary Figure S5 from Characteristics of a <i>CCL21</i> Gene–Modified Dendritic Cell Vaccine Utilized for a Clinical Trial in Non–Small Cell Lung Cancer

  2025-02-04

  preprintOpen access

  <p>Supplementary Figure S5. Functional impact of lymphocyte subpopulations in CCL21-DC vaccines.</p>

  PublisherOA PDFDOI

• ImmunoDriver-1: Driver alterations (dAlts) and their immunological implications in early and metastatic non-small cell lung cancer (NSCLC).

  Journal of Clinical Oncology · 2025-05-28

  article

  8060 Background: NSCLC treatments and clinical trials include targeted agents and immunotherapy (IO) across stages, yet dAlts and how they relate to the tumor immune microenvironment (TIME) are incompletely characterized in early NSCLC (eNSCLC; stage I-III) and metastatic NSCLC (mNSCLC; stage IV). Here, we evaluated the NSCLC TIME by dAlt status to inform IO biomarker strategies. Methods: From the Tempus Database, we selected de-identified lung adenocarcinoma samples sequenced by xT DNA assay (eNSCLC n=5,535; mNSCLC n=10,299), a subset with whole transcriptome analysis. Targetable dAlts were defined as classic (c) (L858R and exon 19 del) or non-classic (nc) EGFR , KRAS G12C, other non-G12C variants, other guideline defined dAlts (ALK, ROS1, RET, NTRK1-3 fusions, ERBB2 alt, METex14), or no dAlt. Immune cell proportions were estimated by quanTIseq. Additional markers, PD-L1 TPS (IHC) and TMB (mt/mB; DNAseq) were analyzed. Significance (p&lt;0.05) was assessed using χ 2 or Wilcoxon/Kruskal-Wallis rank sum tests. Results: The dAlt prevalence was similar (|Δ| &lt; 2%) across early and late stage (Overall %: cEGFR=13, ncEGFR=2.9, KRAS G12C=15 and KRASother=22). The prevalence of other dAlt were less than 4% across stages. The CD8 proportion was higher in eNSCLC than mNSCLC (p&lt;0.001). Across stages, CD4 Treg and CD8 proportions in the KRAS G12C cohort were nearly identical to the non-dAlt cohort, while c/nc EGFR tumors exhibited the lowest percentage of CD8 cells and higher Tregs cells compared to non-dAlt tumors (Table). PD-L1 and TMB were similar between KRAS G12C and non-dAlt tumors and lowest among c/nc EGFR (Table). Conclusions: This real-world analysis demonstrated similar dAlt prevalence across eNSCLC and mNSCLC, while the TIME was distinct across stage and dAlts. The TIME of KRAS G12C tumors was similar to non-dAlt tumors, and was least immunogenic in the c/nc EGFR cohort. These findings highlight immunological differences across stages and dAlts that should be considered when developing IO strategies. Group IO marker Overall No dAlt cEGFR ncEGFR KRAS G12C KRAS other Other dAlt eNSCLC % CD8 cells 1 * 1.3 (0.5, 2.4) 1.4 (0.6, 2.8) 0.9 (0.4, 1.7) 1.0 (0.5, 1.9) 1.4 (0.6, 2.6) 1.3 (0.5, 2.4) 1.1 (0.5, 2.1) % Tregs 1 * 6.9 (4.8, 9.2) 6.3 (4.2, 8.8) 7.4 (5.6, 9.4) 8.2 (5.8, 10.3) 7.0 (5.1, 9.3) 7.1 (5.2, 9.3) 6.7 (4.6, 8.6) % PDL1 2 * 22 20 9.3 7.9 31 25 24 TMB* 5.8 (3.2, 9.5) 7.9 (3.7, 13.2) 3.2 (2.1, 4.7 4.2 (2.3, 6.3) 6.8 (4.2, 10.0) 5.8 (3.7, 8.9) 3.2 (1.6, 5.3) mNSCLC % CD8 cells 1 * 0.6 (0.04, 1.6) 0.8 (0.1, 1.9) 0.4 (0.0, 1.3) 0.5 (0.0, 1.5) 0.7 (0.1, 1.7) 0.5 (0.01, 1.5) 0.5 (0.0, 1.4) %Tregs 1 * 4.0 (2.6, 5.9) 3.8 (2.4, 5.6) 4.2 (2.9, 6.1) 4.7 (3.0, 6.8) 4.2 (2.7, 6.0) 4.0 (2.6, 6.0) 3.9 (2.6, 5.6) % PDL1 2 * 28 24 15 17 37 34 34 TMB* 5.8 (3.2, 10.0) 7.9 (4.2, 13.1) <jats:td colspan="1" rowspan=

  PublisherDOI

• Abstract A033: <i>In situ</i> vaccination with <i>Flt3l</i> gene-modified CD103+ type 1 conventional dendritic cells (cDC1) in murine models of non-small cell lung cancer (NSCLC)

  Cancer Immunology Research · 2025-02-23

  articleSenior author

  Abstract A major hurdle in treatment of Non-small cell lung cancer (NSCLC) with anti-PD-1 immune checkpoint blockade (ICB) therapy is a lack of response (primary resistance) and relapse after an initial response (acquired resistance). Recent studies reveal that responses to PD-1/PD-L1 blockade are associated with high tumor mutational burden (TMB), increased CD8+ T cell infiltration, and high baseline PD-L1 expression within the tumor microenvironment (TME), while impaired tumor antigen presentation and the immunosuppressive TME have been associated with ICB resistance. Numerous studies have established that the generation of an anti-tumor immune response driven by CD8+ T cells requires type I conventional dendritic cell (cDC1) mediated cross presentation of tumor associated antigens, which can license CD8+ T cells to initiate an anti-tumor immune response. In addition, previous publications have shown that systemic administration of the FMS-like tyrosine kinase 3 ligand (FLT3L) cytokine can expand endogenous cDC1s in the TME and augment anti-tumor immune responses to ICB therapy. Considering these data, we hypothesize that a viable approach to overcome NSCLC anti-PD-1 resistance is to intratumorally vaccinate tumors with Flt3l-gene modified cDC1s. Using lenti-viral transduction, we engineered murine CD103+ cDC1s to constitutively secrete FLT3L (FLT3L_cDC1) and performed in situ vaccination studies on murine models of NSCLC with Lkb1-deficiency and elevated TMB that better represents human disease. In situ vaccination with FLT3L_cDC1 promotes anti-tumor immune responses in NSCLC tumors that are non-responders to unmodified cDC1 vaccination and synergizes with anti-PD-1 ICB to significantly inhibit tumor growth. FLT3L_cDC1 therapy induces significant activation and expansion T cells within the TME at both an early and late timepoint post vaccination. Furthermore, FLT3L_cDC1 + anti-PD-1 combination therapy significantly increases DC progenitor numbers within the tumor draining lymph node, including DC progenitors that are committed to the cDC1 lineage. NSCLC tumor bearing mice cured following FLT3L_cDC1 + anti-PD-1 therapy independently reject rechallenge with the same NSCLC tumor model, suggesting that combination therapy promotes tumor-specific immune memory responses. Our data suggests in situ vaccination with FLT3L_cDC1 represents a promising strategy to potentiate the efficacy of ICB and can improve outcomes for patients with primary resistance to PD-1/PD-L1 monotherapy. Citation Format: Jensen Abascal, Ramin Salhi-Rad, Michael S Oh, William P Crosson, Camelia Dumitras, Bin Liu, Steven M Dubinett. In situ vaccination with Flt3l gene-modified CD103+ type 1 conventional dendritic cells (cDC1) in murine models of non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A033.

  PublisherDOI

• Supplementary Table 1 from Noninvasive Lung Cancer Subtype Classification Using Tumor-Derived Signatures and cfDNA Methylome

  2025-03-28

  supplementary-materialsOpen accessSenior author

  &lt;p&gt;Clinical information of the tissue and blood samples&lt;/p&gt;

  PublisherOA PDFDOI

• Supplementary Figure 1 from Noninvasive Lung Cancer Subtype Classification Using Tumor-Derived Signatures and cfDNA Methylome

  2025-03-28

  preprintOpen accessSenior author

  &lt;p&gt;Fragment-based marker discovery between LUAD and LUSC&lt;/p&gt;

  PublisherOA PDFDOI

• Supplementary Figure S2 from Characteristics of a &lt;i&gt;CCL21&lt;/i&gt; Gene–Modified Dendritic Cell Vaccine Utilized for a Clinical Trial in Non–Small Cell Lung Cancer

  2025-02-04

  preprintOpen access

  &lt;p&gt;Supplementary Figure S2. Comparison of CCL21-DC vaccine batches from the same patient.&lt;/p&gt;

  PublisherDOI

• Abstract B092: Mechanisms of PARP7 inhibition-induced tumor cell death: A novel therapeutic for non-small cell lung cancer with tumor-intrinsic and immune-dependent pathways

  Cancer Immunology Research · 2025-02-23

  articleSenior author

  Abstract Poly-adenosine diphosphate (ADP)-ribose polymerase 7 (PARP7) is an enzyme that postranslationally modifies target proteins with an ADP-ribose group, which is required for multiple cellular processes, including DNA repair, immune function, and cellular metabolism. Recent studies have identified a subset of non-small cell lung cancer (NSCLC) exhibiting cancer dependency to PARP7, suggesting that PARP7 may be a therapeutic target for NSCLC. In addition, PARP7 was recently identified as an immune evasion mechanism for cancer cells to escape immune surveillance by dampening the type I interferon (IFN) response to nucleic acid sensors. Targeted inhibition of PARP7 by a small molecule inhibitor, RBN-2397, restored type I IFN signaling to nucleic acid sensing signals, inducing both tumor intrinsic cell death and immune activation that together led to tumor regression. However, the specific signaling mediators of PARP7 inhibition (PARP7i)-mediated tumor cell death and host immune activation remain unknown. In addition, because PARP7 dependency in NSCLC is not driven by genomic mutations, biomarkers of sensitivity/resistance to PARP7 have not been identified. Thus, there is a critical demand for mechanistic studies of PARP7i and biomarker identification of PARP7 sensitivity for patient stratification of future trials. To identify the mechanistic signaling mediators involved in tumor regression mediated by PARP7i, we performed a single cell RNA-sequencing assay on PARP7 sensitive and resistant NSCLC cell lines treated with RBN-2397, and identified top 10 candidate differentially expressed genes (DEGs) that may play a role in the PARP7i-induced killing of tumor cells. We established single gene knockouts (KO) of the top 3 genes in a NSCLC sensitive cell line using the CRISPR-Cas9 technology to determine the functional role of these DEGs in PARP7i-induced tumor intrinsic cytotoxicity. Preliminary data suggests there are multiple pathways involved in PARP7i-mediated tumor cell death. In parallel, we designed a CRISPR pool library KO screen to probe hundreds of candidate signaling molecules using an enrichment-based assay. To identify potential biomarkers of PARP7 dependency in human NSCLC patients, we assessed PARP7 dependency of primary tumor surgical resections from NSCLC patients in both 2D cell culture and 3D Patient Derived Organoids (PDOs) using an optimized drug dose response proliferation assay. We will further probe for molecular and genetic differences between PARP7 dependent vs independent phenotypes to identify potential biomarkers for PARP7 dependency. These studies will elucidate the signaling mediators and uncover new mechanisms by which PARP7i leads to anti-tumor effect via both tumor-intrinsic and immune regulatory pathways, and identify potential biomarkers of PARP7 dependency that will facilitate effective patient stratification for future trials evaluating PARP7 inhibitors as a potential therapy for NSCLC. Citation Format: Nalani J. Coleman, Ji-Ann Lee, Camelia Dumitras, Gauri Gusain, Dylan Conklin, Michael Palazzolo, Bitta P. Kahangi, Austin K. Rennels, Jensen Abascal, William P. Crosson, Michael S. Oh, Edgar Perez Reyes, Carlos Botero, Hong Jiang, Alvaro Chumpitaz Lavalle, Shahed Tappuni, Emily Melik Aslanian, Jie Deng, Ramin Salehi-Rad, Linh M. Tran, Kostyantyn Krysan, Bin Liu, Steven M. Dubinett. Mechanisms of PARP7 inhibition-induced tumor cell death: A novel therapeutic for non-small cell lung cancer with tumor-intrinsic and immune-dependent pathways [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B092.

  PublisherDOI

Recent grants

• Clinically Actionable Neoantigens in Non-Small Cell Lung Cancer

  NIH · 2012–2021

• The UCLA Pulmonary and Critical Care Medicine Scientist Training Program (PCCM-STP)

  NIH · $8.0M · 2003–2030

• NIH Grant R21CA105705

  NIH · $671k · 2010

• NIH Grant P50HL067665

  NIH · $9.5M · 2006

• NIH Grant KL2TR000122

  NIH · $4.5M · 2016

Frequent coauthors

• Sherven Sharma

  500 shared

• Kostyantyn Krysan

  300 shared

• Tonya C. Walser

  221 shared

• Avrum Spira

  Boston University

  207 shared

• David Elashoff

  University of California, Los Angeles

  166 shared

• Marc E. Lenburg

  Boston University

  149 shared

• Edward B. Garon

  143 shared

• Linh M. Tran

  University of California, Los Angeles

  137 shared

Labs

• Steven M. Dubinett LaboratoryPI