Postdoctoral Training

Contact us

Carol Lange, Ph.D.
Director, Cancer Biology Training Grant
University of Minnesota Medical School
Mayo Mail Code 806
420 Delaware St. SE
Phone: 612-626-0621 Fax: 612-624-3913
E-mail: lange047@umn.edu

The postdoctoral training program is designed to provide training in the conduct of scholarly investigation in one of the four scientific areas of expertise of the Cancer Biology Training Grant preceptors. The training is designed for biomedical scientists who have a Ph.D. in basic science (biochemistry, cell biology, genetics, microbiology, immunology, etc.) and for physicians who have basic research experience and interest in the areas studied by the preceptors. Support for postdoctoral trainees is typically for two years. However, all postdoctoral trainees are encouraged to apply for independent postdoctoral funding while they are being supported on the training grant.

Interested postdoctoral fellows currently training in a preceptor's laboratory may apply for support on the Cancer Biology Training Grant when a position becomes available. All positions are selected on a competitive basis by the Cancer Biology Training Grant Steering Committee. Contact the Cancer Biology Training Grant Director for information on how to apply.

If you are interested in postdoctoral training with one of our preceptors, you may contact them directly or direct an inquiry to Carol Lange, Ph.D. at lange047@umn.edu

Chelsea Lassiter, PhD

Chelsea Lassiter, PhD

Schwertfeger lab
Phone: 612-626-5059
Email: classite@umn.edu

Immunotherapy has shown promise in some solid tumors including breast cancers with high levels of tumor infiltrating lymphocytes (TILs). In other cancers, enhancing T cell infiltration into tumors that lack significant levels of TILs enhances responsiveness to immune based therapies (TILs). TIL infiltration is found in approximately 20% of triple negative breast cancers (TNBCs) and correlates with favorable patient outcome. Therefore, developing approaches to enhance T cell infiltration into primary and metastatic lesions could enhance the percentage of breast cancer patients that respond to immunotherapy.

The signal transducer and activator of transcription (STAT) protein family regulates gene expression changes related to proliferation, apoptosis, and immune response. Constitutively active STAT3 is found in 70% of human solid tumors and regulates immune response to tumor cells.  STAT3 is a potent oncogene and a promising target for immunotherapy. Our lab has shown that a loss of STAT3 leads to an increase in a potent tumor suppressor, STAT1, in multiple cell types. There is also an increase in immunomodulatory genes. In addition, we see a compensatory increase in an immune checkpoint protein, PD-L1, expressed by tumor cells and macrophages

We predict that STAT3 inhibition will enhance T cell infiltration into tumors through increased expression of T cell chemokines, although this will not be sufficient to elicit an anti-tumor response due to increased PD-L1 expression. Therefore, we hypothesize that selectively inhibiting STAT3 and PD-L1 will increase recruitment and enhance activation of T cells at the tumor site, and lead to an effective anti-tumor immune response. 

 

Milagros Silva Morales, PhD

Milagros Silva Morales, PhD

Mueller lab
612-625-8614
Email: silva271@umn.edu

Peripheral Immune Self-Tolerance Mechanisms: Anergy, Treg cells and Cancer
Peripheral tolerance is a necessary mechanism to control auto-reactive lymphocytes outside of the thymus. Anergy is a peripheral tolerance mechanism wherein self-reactive lymphocytes become unresponsive after antigen encounter but remain alive. Anergic CD4+ T cells lose their ability to produce growth factors such as IL-2 in response to antigen and develop poor proliferation. Recently, our laboratory reported on an anergic subset of naturally occurring Foxp3CD44hiCD73hiFR4hi polyclonal CD4+ T cells in healthy hosts. Responder CD4+ T cells with this phenotype could also be induced in response to recognition of fetal anti­gens during pregnancy. Interestingly, more than 80% of anergic T cells also specifically expressed the semaphorin receptor Nrp1 by day 18 of pregnancy. Foxp3+ Treg cells are also essential for peripheral immune tolerance and for anergy induction. Remarkably, polyclonal anergic CD4+ T cells can be induced to differentiate into Treg cells when they are adoptively transferred to a lymphopenic host. In particular, Nrp1+ anergic conventional CD4+ T cells displaying a partially de-methylated tTreg-me signature gave rise to functional Foxp3+Nrp1+ pTreg cells with a fully de-methylated Treg-me signature in vivo.

T cell anergy is proposed to be a cellular mechanism of immune evasion contributing to the failure of T cells to eradicate tumors. Tumor antigens can be taken up and presented by APCs in the absence of co-stimulatory signals promoting anergy in antigen-specific CD4+ T cell populations. In addition to anergy, regulatory T cells also have a principal role in promoting immune evasion by cancer cells. Foxp3+ Tregs are specifically recruited to the tumor sites and suppress tumor-specific T cell responses. Their abundant presence is one of the major obstacles to effective antitumor immunotherapy and it is often associated with poor clinical prognosis. In spite of these important discoveries the role of Treg in cancer is controversial. Finally, Nrp1 up-regulation appears to be associated with the tumor invasive behavior and metastatic potential. Increased levels of Nrp1 correlate with tumor aggressiveness, advanced disease stage, and poor prognosis.

Our hypothesis for why Treg cells arise in tumors is that Nrp1+ anergic CD4+ T cells are ideal progenitors for Foxp3+ Treg cells. The objective of my project is to specifically study the role of Nrp1 on the induction of CD4 T cell anergy and the trans-differentiation of anergic conventional T cells into the Foxp3+ Treg cell lineage.

Lynsey Fettig, PhD

Lynsey Fettig, PhD

Yee Lab
612-625-2838

Kelly Makielski, PhD

Kelly Makielski, PhD

Modiano Lab
Email: makie001@umn.edu

Osteosarcoma (OSA) is an uncommon but devastating bone cancer, typically diagnosed in children and adolescents. Despite aggressive treatment, many affected children develop metastatic disease for which there is no effective therapy. Despite advances in cancer therapy, the prognosis with OSA has remained stagnant for over thirty years, highlighting the need for novel treatment strategies. OSA is an immune responsive tumor, making immunotherapy a promising new treatment. One approach to activate the immune system is with oncolytic viruses, such as vesicular stomatitis virus (VSV). Oncolytic viruses selectively replicate in and destroy tumor cells, exposing viral antigens and tumor-associated antigens, triggering an anti-tumor immune response to potentially delay or prevent metastases.

Pediatric OSA research is hindered by its rarity, with fewer than 1,000 new cases diagnosed annually. In contrast, OSA occurs commonly in dogs, and its comparable clinical presentation makes the dog a useful model for translational OSA research. We have previously shown the existence of two molecular OSA phenotypes with distinct biological behavior and prognosis, characterized by both intrinsic tumor properties and host factors. This provides the opportunity to test experimental therapies on two disease phenotypes expected to have different prognoses with standard of care alone.

We are investigating the potential of oncolytic virotherapy with VSV to initiate anti-tumor immunity in canine OSA, with the intent to inform future clinical trials for human patients. Dogs with naturally-occurring OSA will be administered oncolytic VSV in addition to standard of care. We will characterize the anti-tumor immune response induced by VSV, and correlate it with the presence of resident or infiltrating immune cells in the tumor, as well as with clinical endpoints, including time to metastasis and survival time.

We hypothesize that VSV treatment will increase infiltration of immune cells into tumors, generating clonal populations with anti-tumor activity. We anticipate that this immune activation will be associated with improved survival compared to that expected with standard of care alone.Our results will provide valuable information regarding the mechanisms of immune activation by VSV and its potential translation to humans with OSA and other tumors. Determining prognostic factors will help guide treatment decisions, targeting VSV therapy primarily toward patients expected to respond favorably.

Ethan Aguilar, PhD

Ethan Aguilar, PhD

Blazar Lab
eaguilar@umn.edu 
 
Hematopoietic stem cell transplantation (HSCT) is used to treat hematological malignancies, but can result in graft-versus-host disease (GVHD) due to donor T cell activation primed to attack the recipient’s normal tissue. GVHD, especially chronic GVHD (cGVHD) is often inversely correlated with tumor relapse. Regulatory T cells (Treg) are a T cell subset with suppressor function, and represent an essential immune regulatory mechanism. GVHD results in persistent Treg reduction. Four first-in-human studies at the UMN have shown Treg capable of reducing albeit not eliminating GVHD when given in high numbers. Because of their immunosuppressive nature, Treg can have a negative impact on graft-versus-leukemia (GVL) responses. The perfect therapeutic to prevent or treat GVHD would be able to limit the extent of GVHD while not impeding GVL responses. Such has been shown for Treg in preclinical models and recently observed in the clinic.
 
Metabolic regulation of the immune system is a burgeoning area of study. A dearth of information exists about the complex, dynamic metabolic processes utilized by different immune cell types that can contribute to anti-tumor effector responses. Treg are known to be highly dependent upon mitochondrial activity and increase fatty acid oxidation (FAO) to meet their energy needs. This suggests strategies that aim to enhance FAO in Treg could lead to enhanced Treg activity and survival, thereby reducing Treg production requirements while increasing their therapeutic index. Mitochondria are the site wherein FAO occurs. The cell cytoskeleton can support mitochondrial fusion that increases FAO by enhancing their motility or fission that is a less robust source of FAO. My novel approach explores a previously unrecognized link between signaling proteins, cytoskeletal dynamics and control of Treg metabolic reprogramming. Thus, the underlying hypothesis of my project is that cytoskeletal structure(s) control Treg function and by targeting such structural components, mitochondrial function and FAO will be increased, leading to heightened potency and protection from GVHD lethality without loss of GVL

More postdoctoral fellowship opportunities

Numerous NIH fellowship opportunities are available in the Masonic Cancer Center and throughout the Academic Health Center for predoctoral and postdoctoral fellows currently training in laboratories of faculty at the University of Minnesota. Candidates not currently working at the U of M can contact training grant directors and faculty preceptors direcly by clicking on the links below to find out about available positions: