The Hu Laboratory

Dr. Tianxiang Hu received his PhD in Developmental Biology from Wuhan University, China. In 2011, he joined the Medical College of Georgia as a postdoctoral fellow studying transcriptional regulation by long non-coding RNA from Human Endogenous Retroviruses in Hematopoiesis. In 2016, he began to work on blood malignancies driven by different chromosome translocations in the Georgia Cancer Center, where he was promoted to Research Scientist and then Assistant Professor. His laboratory uses unique mouse models of Chronic Myeloid Leukemia (CML) carrying BCR-ABL1 (Philadelphia (Ph) chromosome), Acute Myeloid Leukemia (AML) carrying CBFB-MYH11 and FLT3-ITD,  as well as Myeloid/Lymphoid neoplasms with FGFR1 rearrangement (MLN-FGFR1; also known as Stem Cell Leukemia/Lymphoma (SCLL) syndrome), to investigate molecular mechanisms regulating leukemia initiation and progression. His most recent research endeavors focus on investigating the mechanisms underlying immune evasion processes during leukemia progression, with the hope of developing novel cancer therapies based on these new discoveries. 

• Mechanisms of immune evasion in blood cancer 

My lab performed the very first comprehensive investigation of the mechanisms of immune evasion during CBFB-MYH11 AML progression. Immune profiling confirmed a global immune suppression during leukemia progression by the leukemia cells. Using a combination of bulk and single cell RNA-Seq, CUT&RUN and ChIP-Seq, we further revealed that mechanistically, CBFB-MYH11 directly binds to promoters and activates critical immune suppression genes including TGFβ and PD-L1 in both mouse and human AML cells, which suppress the antitumor immune response to ensure leukemia progression. We also revealed that there was global immunosuppression during CML initiation and progression, which was directly driven by BCR-ABL1 expressing CML cells. On one hand, the BCR-ABL1 oncogene drives the differentiation of leukemia cells toward the neutrophil lineage. On the other hand, the oncogene also transcriptionally activities master immune regulators, including arginase and TGF-β through C/EBPβ. Therefore, combination therapy targeting both leukemia cells and exhausted T cells provides rapid remission and delayed relapse in a preclinical mouse CML model. 

• Development of novel immunotherapies for leukemia

Our basic mechanism study revealed that CBFB-MYH11 oncogene directly upregulates both TGFB1 and CD274 (encoding PD-L1) to orchestrates this immune evasion process, providing a very strong rationale to a novel dual-targeting strategy of PD-L1/PD-1 and TGFβ for immunotherapy of CBFB-MYH11 AML. Targeting both PD-L1/PD-1 (to reactivate exhausted T cells) and TGFβ (to reverse its broad immunosuppressive effects, including T cell exclusion and suppression) may offer a synergistic strategy. Blocking TGFβ could potentially "prime" the tumor microenvironment, making it more permissive for T cell infiltration and function, thus enhancing the efficacy of PD-1/PD-L1 blockade. Considering the potential that immunotherapy alone may not be sufficient for initial bulk tumor reduction in aggressive diseases like AML, we are also actively evaluating whether combination of chemotherapy (cytarabine) with novel PD-L1/TGFβ dual targeting regents could provide superior disease control and even disease-free survival.  Using the humanized HLA-A*02:01 (A2) transgenic mouse CML model, we have demonstrated that CD8 T cells are responsible for efficient eradication of all BCR-ABL1 expressing leukemia cells in recipient mice after primary CML cell transplantation, using both antibody mediated CD8 T cell depletion and adoptive T cell transfer experiment. Furthermore, rechallenge experiments in CML-inoculated, but leukemia-free mice, revealed that they were completely protected against a new tumor challenge. Importantly, we successfully identified 3 epitopes derived from the BCR-ABL1 oncogene that can be efficiently presented by A2 molecules and confirmed a direct CD8 T cell mediated clearance of Ph+ leukemia cells upon the recognition of the BCR or ABL1 antigens. We are actively cloning and studying the antitumor function of a panel of TCRs with different affinities, hoping to obtain the optimal TCRs to create TCR-Ts of potent antitumor effect with tolerable toxicity that can be used for the treatment of CML and even all Ph+ ALL and AML. 

• Immune modulation role of neutrophils in cancer & aging

Tumor associated neutrophils (TANs) increase in the microenvironment in response to the presence of tumors and suppress antitumor immunity. Characterization of these TANs, however, has mostly focused on solid tumors. Single cell sequencing of microenvironment cells during the development of leukemias driven by FGFR1 fusion kinases has identified six distinct subgroups of neutrophils but only two, Ly6g and Camk1d expressing neutrophils, show a dramatic increase in response to leukemogenesis. In depth molecular characterization of these leukemia responsive neutrophils revealed unique gene signatures.  Noticeably, the matrix metalloproteinase (MMP) genes, Mmp8 and Mmp9, are upregulated in the Ly6g+ and Camk1d+ neutrophils during leukemia progression. Pharmacological inhibition of MMPs using Ilomastat restricts in vitro migration of TANs and suppresses their mobilization from the bone marrow with a significantly improved survival in vivo. Clinical correlative analysis reveals that MMP8 is an independent indicator for poor prognosis in AML patients and correlates with higher neutrophil infiltration and poor pan-cancer prognosis. MMP inhibition, therefore, suggests a possible therapeutic approach by targeting TAN mobilization and recruitment for both leukemias and solid tumors. In addition, we were able to establish a neutrophil scoring system based on the gene signatures defined from leukemia associated neutrophils, which can independently predict the prognosis of newly diagnosed AML patients.