Graft-versus-host disease (GVHD) is the leading cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation, an established therapy for patients with hematological malignancies. Current strategies to diminish GVHD include T-cell depletion and immunosuppressive drugs, which are associated with an increased risk of tumor relapse, opportunistic infection, and/or toxicity. Novel approaches acting intrinsically on the immune system are clearly needed. The focus of my research is to harness the suppressive function of myeloid-derived suppressor cells (MDSCs) for the treatment/prevention of graft-versus-host diseases (GVHDs) and to study the mechanisms underlying the differential regulation of GVHD and graft-versus-leukemia/lymphoma (GVL) activities by myeloid-derived suppressor cells (MDSCs). The ultimate goal of my research is to identify signaling pathways and targets that regulate the functional activities (immunostimulatory versus immunosuppressive) of MDSCs. The information garnered from these studies can be utilized for the treatment of cancer, autoimmune, and viral infectious diseases.
Myeloid-derived suppressor cells (MDSCs) suppress T-cell responses through multiple mechanisms. We demonstrated that MDSCs induced antigen specific T regulatory cells and T-cell anergy in vivo. The unique suppressive function of MDSCs endows them with potential clinical merits. While it is widely accepted that MDSCs offer an appealing target for therapeutic intervention in cancer treatment, a growing body of evidence suggests that MDSCs per se have great therapeutic potential in the pathologic settings where deleterious or excessive immune responses need to be avoided or reduced. We have demonstrated that upon adoptive transfer, MDSCs can efficiently prevent graft-versus-host disease (GVHD) without compromising the graft-versus-leukemia effects (GVL) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) in murine models. Recently we also demonstrated that MDSCs acquire M1 or M2 functional macrophage phenotypes through agonism and antagonism of myeloid inhibitory receptor signaling, which may facilitate the development of antitumor responses or mediate immune suppression and Treg activation, respectively. We hypothesize that: (i) The functional phenotype of MDSC can be modulated by PIR-BL ligation and (ii) the presence of MDSCs with a persistent M2 functional phenotype may be sufficient to prevent GHVD and retain GVL ability.
Cancer stem/initiating cells and chemoresistance
Cancer initiating cells exhibit distinct markers and are highly tumorigenic. Several research groups have successfully isolated colorectal cancer initiating cells (CCICs) based on distinct cell-surface markers. Conventional therapies, including chemotherapies and radiotherapies, target the bulk population of rapidly proliferating colorectal cancer cells. Although a large proportion of tumor mass is eradicated, therapy-resistant CCICs remain and can differentiate into colon cancer cells. Repopulation of the tumor over time by the progenies of CCICs ultimately results in a more aggressive phenotype than the initial pretreated malignancy. With 56,500 fatalities per year, colorectal cancer is second only to lung cancer as a cause of cancer deaths in the USA. Each year, 150,000 to 160,000 new cases are diagnosed of which 10 to 20% already have liver metastases. About 70% of all colorectal cancer patients eventually develop liver metastases. Hepatic resection is currently the only form of treatment that offers long-term survival, with 5-year survival rates ranging from 25% to 39%. Using the current selection criteria for hepatectomy, only 10% to 20% of all patients are candidates for curative operation. The prognosis for the remaining patients is grim with palliative chemotherapy and symptomatic treatments being the only available options. There are no reliable treatment modalities for controlling cancer recurrence after chemotherapy. Our laboratory has found that myeloid inhibitory receptors play an important role in controlling the “stemness” of colon cancer initiating cells and induction of epithelial-mesenchymal transition (EMT). We found that activation of myeloid inhibitory receptor promoted acquisition of an M2 (alternative) macrophage functional phenotype by myeloid-derived suppressor cell, induced “stemness” phenotypes of colon tumor cells, and enhanced metastases. We hypothesize that myeloid inhibitory receptor activation can induce the phenotype of colon cancer initiating cell and EMT, thereby facilitating the development of chemotherapy resistance. Our study will identify the molecular determinants of myeloid inhibitory receptor-mediated signaling in control of CCIC and EMT phenotypes, and provide new information for devising a novel therapeutic modality for refractory colorectal cancer.
Research Directions:
1. Study the regulatory pathways of MDSC function and the associated effects on GVHD.
2. Study the mechanism of MDSC mediated differential regulation of alloimmunity (GVHD vs. GVL) in pre-existing tumor models.
3. Study the effects of myeloid inhibitory receptor activation through agonistic antibodies on MDSC as related to MDSC suppressive function, inhibition of GVHD, and the corresponding signaling regulation.
4. Study the mechanism and effects of MDSC mediated regulation of GVHD vs. GVL through myeloid inhibitory receptor activation in mouse GVHD models and in a human xenograft NSG mouse model.
5. Study whether the GVT effect in allogeneic bone marrow transplantation can be used to eradicate metastatic cancers that cannot be successfully eliminated by operation, chemotherapy, or radiation therapy.
6. Study the molecular mechanisms underlying the regulation of colon cancer stemness, EMT, and chemoresistance by myeloid inhibitory receptors ectopically expressed by tumor cells.
7. Determine the effect of myeloid inhibitory receptor antagonism on stemness and EMT phenotype of colon cancer.
8. Assess the therapeutic efficacy of myeloid inhibitory receptor antagonism in combination with chemotherapies for the treatment of colon cancer in xenograft mouse models of human colon cancer.
