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Transplantation Immunology

Caption available
Picture of Th17 cells infiltrating the lung in a mouse model of acute GvHD. Figure chosen for Blood Journal cover (5 February 2009; Volume 113; Number 6).

Graft versus Host Disease (GvHD)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is used to treat a number of malignant and nonmalignant diseases such as multiple myeloma and aplastic anemia. Patients are administered radiation or chemotherapy before the transplant to destroy the malignant or unhealthy cells. Radiation and chemotherapy can also destroy the recipient’s bone marrow and immune system, and allo-HSCT is performed to replace the destroyed bone marrow with healthy cells. However, a major complication of allo-HSCT is graft versus host disease (GvHD). GvHD is a severe inflammatory disease caused by donor T cells recognizing recipient organs and tissues as foreign and mounting an immune response against them causing damage. Current treatment for GvHD is an immunosuppressive drug regimen that can predispose patients to opportunistic infections. Therefore, it is of critical importance to further develop and understand the underlying mechanisms that mediate GvHD pathogenesis in efforts to develop novel therapeutic treatments.

Type 2 Innate Lymphoid Cells (ILC2 Cells)

Patients with gastrointestinal (GI) tract GvHD who do not respond to steroids have a poor survival outcome. We are focused on further understanding GI tract GvHD to develop novel therapies to successfully treat steroid non-responsive patients. Utilizing mouse models of GvHD, our lab found that type 2 innate lymphoid (ILC2) cells residing in the lower GI tract are lost after radiation or chemotherapy, and transplantation of donor bone marrow is unable to reconstitute this lost population of cells. Based on this finding, our lab hypothesized that ILC2 cells are critical in protecting against GI tract GvHD. We found that infusion of donor ILC2 cells resulted in increased survival and ameliorated GI tract GvHD compared to mice that did not receive ILC2 cells. ILC2 cell infusion was also associated with decreased inflammation in the lower GI tract. Based on our findings, we believe ILC2 cells might be a promising therapeutic for patients with GI tract GvHD. We are further characterizing the role of third party ILC2 cells in mouse models of GvHD, and we are optimizing conditions to culture and expand human ILC2 cells as part of our preclinical studies.

Cancer Immunotherapy

Immune cells are integral in controlling cancer growth; however, the tumor microenvironment (TME) is immunosuppressive and there are numerous ways the tumor evades immune recognition. Therefore, our group is focused on modulating the immune system to target cancer cells to enhance the anti-tumor immune response.

Chimeric Antigenic Receptor (CAR) T Cells

CAR T cells are genetically engineered to recognize a specific protein on cancer cells to improve antigen recognition for better tumor control. CAR T cell immunotherapy has been successful in treating blood or liquid cancers such as acute lymphoblastic leukemia; however, CAR T cell therapy has not been as successful in treating patients with solid tumors due to limitations in CAR-T cell trafficking and persistence in the TME, exhaustion, and the immunosuppressive nature of the TME. Our lab is focused on optimizing CAR-T cell immunotherapies against solid tumors. Recent work from our lab has found that CAR-T cells generated from Th17 and Tc17 cells along with administration of a STING agonist, which is known to enhance the immune response, successfully controlled tumor growth in a mouse model of breast cancer. We are currently working to improve our technology to develop CAR-T cells that are more persistent in the TME and are resistant to exhaustion, which we think will help to improve outcomes in patients with solid malignancies.

Immune Checkpoint Inhibitor and Nanoparticle Therapy

Checkpoint inhibitory receptors found on the surface of T cells can contribute to T cell exhaustion. Immune checkpoint inhibitor (ICI) therapy blocks the interaction of checkpoint inhibitory receptors and their ligands. ICI therapies, which are antibodies specific to checkpoint inhibitory receptors, have been successful in treating cancer in a subset of patients; however, it is important to try to increase the effectiveness of ICI therapy to help treat a larger number of patients.  Recent collaborative work from our lab and Dr. Andrew Wang’s group demonstrates that nanoparticles conjugated with antibodies specific for checkpoint inhibitors and antibodies that activate co-stimulatory T cell molecules results in increased anti-tumor immune response in a mouse model of cancer through improved T-cell activation and increased immunological memory compared to administration of free antibodies. Currently, we are working on delivering antigenic tumor peptides via nanoparticles in combination with antibody therapy that inhibits immune checkpoint inhibitors and activates immune co-stimulators to try to improve the immune response against tumors.

B cells

In addition to cancer cells, the TME is composed of endothelial cells, fibroblasts and a variety of immune cells, including T and B cells. While much has been elucidated regarding T cells, we have very little understanding of B cell function in the TME. Collaborative research between Dr. Charles Perou’s lab and our lab focuses on better understanding the mechanisms by which immune checkpoint inhibitor (ICI) therapy facilitates an anti-tumor response in a mouse model of triple negative breast cancer (TNBC), and we have found that B cells play a critical role. The anti-tumor response generated by ICI therapy is strongly associated with B cell activation of T cells. Moreover, we found that antibody production was required to respond to dual ICI therapy as mice who could not secrete antibody did not respond as well using mouse models with enhanced number of somatic mutations. Moreover, breast cancer patients who responded to chemotherapy had increased numbers of B cells before treatment, and there was also a positive correlation between the presence of B cells in the TME and patient prognosis suggesting that B cells can be used as a predictor for outcome in patients. Finally, our recent human work has suggested that intrinsic subtypes of breast cancer can be differentiated based on the extent of clonally expanded plasmablasts in the tumor microenvironment.