Laboratory of Masoud Manjili, D.V.M., Ph.D.
Immunotherapy of tumor dormancy
The objective of this project is to identify molecular or cellular events that establish tumor dormancy after chemotherapy and those that lead to disease recurrence. Disseminated tumor cells (DTC) or circulating tumor cells (CTC) that are quiescent have been detected in cancer free patients several years after successful treatment of their primary cancer, as well as in patients with non-metastatic cancer. We have reported that dormant tumor cells become resistant to chemotherapy and radiation therapy primarily because of being quiescent. However, they remain susceptible to immunotherapy. We have also identified two types of tumor dormancy, which include Ki67- quiescent dormancy and Ki67low indolent dormancy. Whereas indolent dormant cells are susceptible to immunoediting and escape from immunotherapy, quiescent dormant cells fail to undergo immunoediting. Our studies suggest that tumor IFN-gamma receptor alpha is a key determinant in the process of tumor immunoediting. Our long-term objective is to develop neoadjuvant, conditioning regimens for dominating a quiescent type of tumor dormancy followed by immunotherapeutic targeting of dormant cells in order to overcome tumor immunoediting and prevent distant recurrence of cancer. Two immunotherapeutic strategies are being evaluated which include adoptive immunotherapy utilizing tumor-sensitized T cells and NKT cells expanded in the presence of gamma chain cytokines, and dormancy-specific DC-based vaccines.
Re-programming tumor-immune crosstalk to overcome tumor escape
Development of cancer in immunocompetent individuals suggests that the host’s immune response, as is, would fail to overcome cancer. Therefore, we propose to induce fundamental changes in the crosstalk between the tumor and immune cells in order to restore tumor immune surveillance. To achieve this objective, we induce epigenetic re-programming of tumor cells in order to convert them into highly immunogenic tumor cells by inducing the expression of new antigens such as cancer/testis antigens (CTA) as well as immunomodulatory molecules such as the death receptor Fas.
Prognostic biomarkers for cancer
Based on our initial correlative observations from an animal model of breast carcinoma as well as from a diverse group of breast cancer patients we have identified a signature of immune function genes in the tumor lesions, which are associated with breast cancer recurrence or relapse free survival. We aim to validate these prognostic and predictive biomarkers through retrospective and prospective studies.
The adaptation model of immunity
Current immunological research and therapeutic approaches for human diseases are inspired by two schools of thought in immunology, which include the self-nonself (SNS) model and the danger model. To explain how an immune response is triggered, the SNS model solely emphasizes on signal I, which is the affinity of T cell receptor for the antigen. The danger model, on the other hand, emphasizes on signal II, which is the expression of co-stimulatory molecules. Although these models are complementary in explaining how an immune response is induced, they cannot explain or predict if an immune response succeeds or fails in eliminating the disease or causing autoimmunity and allergy. Cancer patients often harbor pre-existing anti-tumor immune responses that often fail to protect them from cancer. Similar observations were made in different diseases. For instance, healthy individuals and patients with multiple sclerosis (MS) harbor T cells that recognize myelin basic protein (MBP), but a pathogenic manifestation of the immune response is evident only in an MS patient. The adaptation model of immunity proposes that signal III or communication signaling determines the outcome of the immune response. Signal III is orchestrated through adaptation receptors (AR) and adaptation ligands (AL). Any alterations in the expression of AR on target cells render them susceptible to an ongoing immune response. This model proposes that expression of AR in the tumor microenvironment render the tumor resistant to tumor infiltrating T cells. We seek to identify the AR and AL in order to develop new immunotherapeutic strategies for human diseases.
Manjili MH. A theoretical basis for the efficacy of cancer immunotherapy and immunogenic tumor dormancy: The adaptation model of immunity. Adv Cancer Res 2018 (in press)
Aqbi HF, Manjili MH. IFN-γ orchestrates tumor elimination, tumor dormancy, tumor escape and progression. J Leukoc Biol 2018 (in press)
Shah SA, Zarei M, Manjili SH, Guruli G, Wang XY, Manjili MH. Immunotherapy of cancer: targeting cancer during active disease or during dormancy? Immunotherapy 9 (11): 943-949, 2017
Benson Z, Manjili SH, Habibi M, Guruli G, Toor AA, Payne KK, Manjili MH. Conditioning neoadjuvant therapies for improved immunotherapy of cancer. Biochem Pharmacol 2017 Aug 10. pii: S0006-2952(17)30534-8. doi: 10.1016/j.bcp.2017.08.007. [Epub ahead of print] PMID: 28803721
Lotfi-Emran S, Ward BR, Le QT, Pozez AL, Manjili MH, Woodfolk J, Schwartz LB. Human mast cells present antigen to autologous CD4+ T cells. J Allergy Clin Immunol 2017 Jun 14. [Epub ahead of print] PMID: 28624612
Manjili MH. Tumor dormancy and relapse: from a natural by-product of evolution to a disease state. Cancer Res 77 (10) 2564-2569, 2017 PMID: 28507050
Sulek J, Robinson SP, Petrossian AA, Zhou S, Goliadze E, Manjili MH, Toor A, Guruli G. Role of epigenetic modification in a murine prostate cancer model. The Prostate 77(4):361-373, 2017 PMID: 27862100
Miller MF, Goodson III WH 3rd, Manjili MH, Kleinstreuer N, Bisson WH, Lowe L. Low-dose mixture hypothesis of carcinogenesis workshop: Scientific underpinnings and research recommendations. Environ Health Perspect 125(2):163-169, 2017 PMID: 27517672
Aqbi HF, Smith TJ, McKiver B, Joshi S, Keim R, Idowu MO, Guo C, Wang XY, Payne KK, Manjili MH. Autophagy and chemotherapy-induced tumor dormancy. Cancer Immunology & Immunotherapy: from conception to delivery. NIH, Washington D.C., October 12-13, 2017.
Aqbi HF, Butler SE, Keim R, Idowu MO, Manjili MH. Chemotherapy-induced tumor dormancy and relapse. IMMUNOLOGY 2017TM AAI Annual Meeting, Washington D.C., May 12-16, 2017.
Smith TM, Butler SE, Wang XY, Manjili MH. Low-dose chemotherapy induces immunogenic tumor dormancy in mouse model of mammary carcinoma cells. IMMUNOLOGY 2017TM AAI Annual Meeting, Washington D.C., May 12-16, 2017. [received 2017 AAI Trainee Poster Award]
Park Y, Hall CE, Scalora AF, Sabo R, Simmons GL, Manjili MH, Clark WB, McCarty JM, Chung HM, Roberts CH, Toor AA. Dynamical system interactions between T cells and monocytes shape alloreactivity following stem cell transplantation. 2017 BMT Tandem Meetings, Orlando, FL, February 22-26, 2017.