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Ping-Ying Pan, PhD

Associate Director, Center for Immunotherapy Research
Houston Methodist


Biography

Ping-Ying Pan, Ph.D., is Associate Director of Cancer Immunotherapy Research Center at the Methodist Research Institute. Prior to joining Houston Methodist, he was an Associate Professor in the Department of Oncological Sciences in the Icahn School of Medicine at Mount Sinai in New York. He obtained his Ph.D. from The University of Texas Health Science Center at San Antonio, Texas in 1996 and finished his postdoctoral training at Department of Medicine, Columbia University. In 2000, he became a senior research associate at Carl C. Icahn Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine (currently Icahn School of Medicine at Mount Sinai, aka ISMMS), and rose to the rank of Associate Professor of the Department of Oncological Sciences, ISMMS in 2009. He has made significant contributions to the fields of cancer immunology and immunotherapy. Dr. Pan has been focusing on studying the mechanisms by which cancer evades immune responses in the tumor microenvironment (TME), more specifically the contribution of myeloid derived suppressor cells (MDSC) to tumor progression. His group is one of the first to demonstrate that MDSCs can act as a “Trojan Horse” in the delivery of oncolytic viruses or therapeutic agents used in direct tumor targeting, thereby preventing tumor metastases. His lab has also demonstrated the use of MDSC, as a cell-based tolerogenic therapy, to suppress unwanted immune responses, such as autoimmunity and graft-versus-host diseases (GVHD), while still retaining graft verse leukemia (GVL) function. More recently, Dr. Pan identified a potential role of myeloid inhibitory receptors in the maintenance of tumor-initiating cells (TIC) and radio/chemo-resistance of colon cancer. Dr. Pan has served on national and international grant review panels and as a reviewer for multiple international journals. His laboratory has published important, high-impact research articles and his research has been continuously supported by NIH grants, private foundations, and pharmaceutical companies.

Description of Research

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” ph

Publications

LILRB receptor-mediated regulation of myeloid cell maturation and function
van der Touw, W, Chen, HM, Pan, PY & Chen, SH 2017, Cancer Immunology, Immunotherapy, pp. 1-9. DOI: 10.1007/s00262-017-2023-x

Leukocyte immunoglobulin-like receptors in human diseases: An overview of their distribution, function, and potential application for immunotherapies
Zhang, J, Mai, S, Chen, H-M, Kang, K, Li, XC, Chen, SH & Pan, PY 2017, Journal of Leukocyte Biology, vol 102, no. 2, pp. 351-360. DOI: 10.1189/jlb.5MR1216-534R

Myeloid-derived suppressor cells as an immune parameter in patients with concurrent sunitinib and stereotactic body radiotherapy
Chen, HM, Ma, G, Gildener-Leapman, N, Eisenstein, S, Coakley, BA, Ozao, J, Mandeli, J, Divino, C, Schwartz, M, Sung, M, Ferris, R, Kao, J, Wang, LH, Pan, PY, Ko, EC & Chen, SH 2015, Clinical Cancer Research, vol 21, no. 18, pp. 4073-4085. DOI: 10.1158/1078-0432.CCR-14-2742

Myeloid-derived suppressor cells as a vehicle for tumor-specific oncolytic viral therapy
Eisenstein, S, Coakley, BA, Briley-Saebo, K, Ma, G, Chen, HM, Meseck, M, Ward, S, Divino, C, Woo, S, Chen, SH & Pan, PY 2013, Cancer Research, vol 73, no. 16, pp. 5003-5015. DOI: 10.1158/0008-5472.CAN-12-1597

Polarization and reprogramming of myeloid-derived suppressor cells
Yang, WC, Ma, G, Chen, SH & Pan, PY 2013, Journal of Molecular Cell Biology, vol 5, no. 3, pp. 207-209. DOI: 10.1093/jmcb/mjt009

Myeloid-derived suppressor cells as a trojan horse: A cellular vehicle for the delivery of oncolytic viruses
Pan, PY, Chen, HM & Chen, SH 2013, OncoImmunology, vol 2, no. 8, e25083. DOI: 10.4161/onci.25083

Myeloid-derived suppressive cells and their regulatory mechanisms in cancer
Ma, G, Pan, PY & Chen, SH 2012, . in Innate Immune Regulation and Cancer Immunotherapy. Springer New York, pp. 231-250. DOI: 10.1007/9781441999146_13

Paired immunoglobin-like receptor-B regulates the suppressive function and fate of myeloid-derived suppressor cells
Ma, G, Pan, PY, Eisenstein, S, Divino, CM, Lowell, CA, Takai, T & Chen, SH 2011, Immunity, vol 34, no. 3, pp. 385-395. DOI: 10.1016/j.immuni.2011.02.004

Myeloid-derived suppressor cells prevent type 1 diabetes in murine models
Yin, B, Ma, G, Yen, CY, Zhou, Z, Wang, GX, Divino, CM, Casares, S, Chen, SH, Yang, WC & Pan, PY 2010, Journal of Immunology, vol 185, no. 10, pp. 5828-5834. DOI: 10.4049/jimmunol.0903636

Development and function of myeloid-derived suppressor cells generated from mouse embryonic and hematopoietic stem cells
Zhou, Z, French, DL, Ma, G, Eisenstein, S, Chen, Y, Divino, CM, Keller, G, Chen, SH & Pan, PY 2010, Stem Cells, vol 28, no. 3, pp. 620-632. DOI: 10.1002/stem.301

Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer
Pan, PY, Ma, G, Weber, KJ, Ozao-Choy, J, Wang, G, Yin, B, Divino, CM & Chen, SH 2010, Cancer Research, vol 70, no. 1, pp. 99-108. DOI: 10.1158/0008-5472.CAN-09-1882

The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies
Ozao-Choy, J, Ge, M, Kao, J, Wang, GX, Meseck, M, Sung, M, Schwartz, M, Divino, CM, Pan, PY & Chen, SH 2009, Cancer Research, vol 69, no. 6, pp. 2514-2522. DOI: 10.1158/0008-5472.CAN-08-4709

Advancements in immune tolerance
Pan, PY, Ozao, J, Zhou, Z & Chen, SH 2008, Advanced Drug Delivery Reviews, vol 60, no. 2, pp. 91-105. DOI: 10.1016/j.addr.2007.08.025

Reversion of immune tolerance in advanced malignancy: Modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function
Pan, PY, Wang, GX, Yin, B, Ozao, J, Ku, T, Divino, CM & Chen, SH 2008, Blood, vol 111, no. 1, pp. 219-228. DOI: 10.1182/blood-2007-04-086835

Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host
Huang, B, Pan, PY, Li, Q, Sato, AI, Levy, DE, Bromberg, J, Divino, CM & Chen, SH 2006, Cancer Research, vol 66, no. 2, pp. 1123-1131. DOI: 10.1158/0008-5472.CAN-05-1299

NK and CD8+ T cell-mediated eradication of poorly immunogenic B16-F10 melanoma by the combined action of IL-12 gene therapy and 4-1BB costimulation
Xu, D, Gu, P, Pan, PY, Li, Q, Sato, AI & Chen, SH 2004, International Journal of Cancer, vol 109, no. 4, pp. 499-506. DOI: 10.1002/ijc.11696

Regulation of Dendritic Cell Function by NK Cells: Mechanisms Underlying the Synergism in the Combination Therapy of IL-12 and 4-1BB Activation
Pan, PY, Gu, P, Li, Q, Xu, D, Weber, K & Chen, SH 2004, Journal of Immunology, vol 172, no. 8, pp. 4779-4789.

Role of Immature Myeloid Gr-1+ Cells in the Development of Antitumor Immunity
Li, Q, Pan, PY, Gu, P, Xu, D & Chen, SH 2004, Cancer Research, vol 64, no. 3, pp. 1130-1139. DOI: 10.1158/0008-5472.CAN-03-1715

In situ recruitment of antigen-presenting cells by intratumoral GM-CSF gene delivery
Pan, PY, Li, Y, Li, Q, Gu, P, Martinet, O, Thung, S & Chen, SH 2004, Cancer Immunology, Immunotherapy, vol 53, no. 1, pp. 17-25. DOI: 10.1007/s00262-003-0417-4

OX40 ligation enhances primary and memory cytotoxic T lymphocyte responses in an immunotherapy for hepatic colon metastases
Pan, PY, Zang, Y, Weber, K, Meseck, ML & Chen, SH 2002, Molecular Therapy, vol 6, no. 4, pp. 528-536. DOI: 10.1006/mthe.2002.0699