Principal Investigator
Xin Lu, Ph.D.
My research integrates mechanistic tumor immunology with translational therapeutics to overcome immune evasion, metastasis, and treatment resistance in solid tumors, with a strong focus on advanced genitourinary malignancies and a particular emphasis on prostate cancer, where the immunologically cold tumor microenvironment has frustrated the application of immune checkpoint blockade that has transformed outcomes in other cancer types. Since establishing my laboratory at the University of Notre Dame, my program has expanded into two interrelated areas: (i) defining cancer cell–intrinsic genetic/epigenetic programs that shape the tumor–immune interactome, and (ii) identifying tractable vulnerabilities in immunosuppressive myeloid cells (particularly neutrophil-lineage suppressor cells, a.k.a, PMN-MDSCs) that limit cytotoxic T cell immunity. I have published over 100 peer-reviewed papers (most of which since starting my lab at Notre Dame), secured extramural funding as PI from NIH/NCI, DoD, and various foundations, and received awards such as the BBA Reviews on Cancer Rising Star Award and the American Cancer Society Coaches vs. Cancer Innovation Award.
A hallmark of my work is uncovering actionable mechanisms by which tumor and host programs impose T cell dysfunction. My laboratory established that neutrophil/PMN-MDSC–like populations are dominant drivers of CD8⁺ T cell exhaustion in several solid tumor settings and defined strategies to curb their immunosuppressive impact. We also developed mechanistic frameworks for tumor-infiltrating neutrophil fitness in stressed microenvironments and demonstrated how metabolic rewiring can be leveraged to enhance immunotherapy. In parallel, we have pursued host-level interventions (e.g., ketogenic regimens/β-hydroxybutyrate supplementation) that reprogram the tumor microenvironment and sensitize otherwise resistant tumors to checkpoint blockade. Across these efforts, we integrate genetically engineered mouse models, functional genomics, experimental therapeutics, and state-of-the-art profiling (single-cell and spatial transcriptomics, multiplex imaging, digital pathology, and multi-omics integration), and our work has been disseminated through invited talks at national and international venues.
Contribution to Science
Targeting Myeloid Immunometabolism and Combinatorial Immunotherapies. My laboratory investigates the mechanistic nodes that sustain immunosuppressive tumor microenvironments (TME) to engineer durable responses to immunotherapy. To address the challenge of "cold" tumors, I pioneered the first chimeric genetically engineered mouse model (GEMM) of metastatic castration-resistant prostate cancer (mCRPC). Using this model, we demonstrated that tumor-infiltrating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) drive resistance to checkpoint blockade and that targeting PMN-MDSCs via CXCR1/2 or PI3K inhibition synergizes with anti-CTLA4/PD1 therapy to eradicate mCRPC (Nature, 2017). To define the biochemical basis of this suppression, we discovered that PMN-MDSCs inactivate T cells through reactive nitrogen species-mediated nitration of the T-cell receptor kinase LCK, linking myeloid metabolism directly to T-cell anergy (PNAS, 2018). Building on this immunometabolic cross-talk, we identified Acod1 as a critical metabolic switch in tumor-associated immunosuppressive neutrophils (iNeu, equivalent to PMN-MDSCs) that drives ferroptosis resistance and promotes metastasis in breast cancer (Cell Metab, 2023). More recently, we demonstrated the translational potential of metabolic interventions, showing that ketogenic diet supplementation can reprogram the epigenetic landscape of prostate cancer to turn "cold" tumors "hot" and overcome checkpoint blockade resistance (Cancer Res, 2024). These studies have established new strategies for combining myeloid-targeted therapies with immune checkpoint inhibitors to elicit durable responses in difficult-to-treat solid tumors.
Chromatin and Epigenetic Regulation of Tumorigenesis and Immune Evasion. My group focuses on the intersection of epigenetics and immunology to identify chromatin effectors that repress tumor antigen presentation and drive metastasis. We posit that chromatin remodelers act as "gatekeepers" of the immune response. A key discovery was the identification of the chromatin effector Pygo2 as a master regulator of the immunosuppressive TME in prostate cancer, achieved through in vivo screening and extensive functional investigation (Cancer Res, 2018; Sci Immunol, 2023). We mechanistically defined that Pygo2 acts via a p53/Sp1/Kit/Ido1 axis to enforce T-cell exclusion; importantly, we showed that targeting Pygo2 creates a "chromatin vulnerability" that synergizes with immunotherapy (checkpoint inhibitor or adoptive T cell transfer), offering a novel therapeutic target for resistant disease (Sci Immunol, 2023). Beyond immune evasion, our work on the opposing roles of TGFβ and BMP signaling and the cooperative function of CHD1 and SPOP has provided critical insights into how dysregulated DNA damage responses and signaling networks drive prostate tumorigenesis. This body of work underscores the potential of epigenetic therapies to not only arrest tumor growth but also re-engage the host immune system.
Molecular Drivers and Translational Models in Renal Cell Carcinoma and VHL Disease. My laboratory utilizes a multi-omics approach to investigate the genomic and metabolic dysregulation driving familial VHL disease and sporadic clear cell Renal Cell Carcinoma (ccRCC). In the realm of precision medicine, we identified a pathogenic synonymous VHL mutation (c.414A > G) that drives hemangioblastoma through a novel splicing mechanism, highlighting that "silent" mutations can have profound clinical consequences. We also linked mitochondrial dysfunction to the Warburg effect in ccRCC, revealing that promoter hypermethylation of UQCRH (a mitochondrial complex III component) accelerates carcinogenesis, offering a new biomarker for metabolic dysregulation. To translate these findings, we characterized global signaling changes upon VHL restoration to identify HIF-independent targets and contributed to the bioengineering of "mini-tumor chips." These microfluidic devices successfully predicted patient-specific immunotherapy responses, representing a significant leap forward in personalized oncology and ex vivo drug screening.
Mechanisms of Organotropic Metastasis and Dormancy in Breast Cancer. My doctoral work uncovered fundamental mechanisms by which disseminated breast cancer cells hijack bone homeostatic circuits to survive, enter dormancy, and eventually thrive as metastases. I defined how cancer cells exploit the "seed and soil" interaction, specifically identifying how VCAM-1 upregulation enables the transition from dormant micrometastases to overt osteolytic lesions by engaging α4β1-positive osteoclast progenitors (Cancer Cell, 2011). This work was instrumental in defining the concept of the "pre-metastatic niche." Furthermore, I elucidated the role of metalloproteinases ADAMTS1 and MMP1, chemokine signaling CCL2/CCR2, and hypoxia in facilitating organ-specific metastasis to the lung and bone. These findings provided a mechanistic basis for the distinct organotropism observed in breast cancer patients and highlighted stromal components as valid therapeutic targets to prevent metastatic outgrowth.
Cell Fusion and Genomic Instability in Tumor Progression. My PhD work also highlighted spontaneous cell fusion as a significant, yet often overlooked, driver of cancer evolution and heterogeneity. I demonstrated that cell fusion events between tumor cells of distinct metastatic organotropism can confer merged organotropism, allowing progeny to inherit distinct metastatic traits from parental lines. We further showed that this process enhances metastatic potential through spontaneous ploidy duplication and cell size enlargement. This research contributed to the "cell fusion hypothesis" of cancer stem cells, suggesting that fusion is a mechanism of rapid somatic evolution that allows tumors to acquire drug resistance and aggressive phenotypes, a concept that continues to inform our understanding of tumor heterogeneity and plasticity.
Complete List of Published Work in MyBibliography:
https://www.ncbi.nlm.nih.gov/myncbi/14A325uGbh1Ab/bibliography/public/
Extra-professional life
I enjoy indoor and outdoor activities with my family. At my leisure time, I write Chinese poems and tune to various styles of music. Below is calligraphic rendering of a few of my poems.
