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. Tumor dormancy and relapse: from a natural by-product of evolution to a disease state. Cancer Res 77 (10) 2564-2569, 2017 PMID: 28507050
Payne KK, Keim RC, Graham L, Idowu MO, Wan W, Wang XY, Toor AA, Bear HD, Manjili MH. Tumor-reactive immune cells protect against metastatic tumor and induce immunoediting of indolent but not quiescent tumor cells. J Leukoc Biol 100(3):625-35, 2016 PMID:26928306
Kravchenko J, Corsini E, Decker W, Williams MA, Manjili MH, Otsuki T, Neetu S, Al-Mulla F, Temaimi R, Amedei A, Colacci AM, Vaccari M, Mondello C, Scovassi I, Raju J, Hamid RA, Memeo L, Forte S, Roy R, Woodrick J, Salem HK, Ryan E, Brown D, Bisson WH, Lyerly HK. Chemical compounds from human environment and immune evasion mechanisms: potential interrelations. Carcinogenesis 36 Suppl 1:S111-27, 2015 PMID: 26002081
Manjili MH. The inherent premise of immunotherapy for cancer dormancy. Cancer Res 74(23):6745-6749, 2014 PMID: 25411346
Manjili MH. The adaptation model of immunity. Immunotherapy 6(1):59-70, 2014. PMID: 24341885
Kmieciak M, Payne KK, Wang XY, Manjili MH. IFN-γ Rα is a key determinant of CD8+ T cell-mediated tumor elimination or tumor escape and relapse in FVB mouse. PLoS ONE 8(12): e82544. doi:10.1371/journal.pone.0082544, 2013. PMCID: PMC3131490.
Payne KK, Zoon CK, Wan W, Marlar K, Keim RC, Nasiri-Kenari M, Kazim AL, Bear HD, Manjili MH. Peripheral blood mononuclear cells of patients with breast cancer can be reprogrammed to enhance anti-HER-2/neu reactivity and overcome myeloid-derived suppressor cells. Breast Cancer Res Treat 142: 45-57, 2013. PMID: 24197563
Ascierto ML, Idowu MO, Zhao Y, Payne KK, Wang XY, Dumur CI, Bedognetti D, Tomei S, Ascierto PA, Shanker A, Bear HD, Wang E, Marincola FM, De Maria A, Manjili MH. NK cell signatures are predictive of relapse free survival in breast cancer patients. J Transl Med 11(1):145, 2013 PMID: 23758773
Toor AA, Payne KK, Chung HM, Sabo RT, Hazlett AF, Kmieciak M, Sanford K, Williams DC, Clark WB, Roberts C, McCarty J, Manjili MH. Epigenetic Induction of Adaptive Immune Response in Multiple Myeloma: Sequential Azacitidine and Lenalidomide to Generate Cancer Testis Antigen Specific Cellular Immunity. Br J Haematol 158(6):700-11, 2012 PMID: 22816680
Berrie ML, Kmieciak M, Sabo R, Roberts C, Idowu MO, Mallory K, Chung H, McCarty J, Borrelli CA, Detwiler MM, Kazim AL, Toor AA, Manjili MH. Distinct oligoclonal T cells are associated with graft versus host disease following stem cell transplantation. Transplantation 93(9):949-957, 2012 PMID:22377792
Ascierto M-L, Kmieciak M, Idowu MO, Manjili RH, Zhao Y, Grimes MM, Dumur CI, Wang E, Ramakrishnan V, Wang X-Y, Bear HD, Marincola FM, Manjili MH. A signature of immune function genes associated with relapse-free survival in breast cancer patients. Breast Cancer Res Treat 131(3):871-80, 2012 PMID: 21479927
Manjili MH and Payne KK. Cancer immunotherapy: re-programming cells of the innate and adaptive immune systems. Oncoimmunol 1(2): 201-204, 2012 PMID: 22720242
Kmieciak M, Basu D, Payne KK, Toor A, Yacoub A, Wang XY, Smith L, Bear HD, Manjili MH. Activated NKT cells and NK cells render T cells resistant to MDSC and result in an effective adoptive cellular therapy against breast cancer in the FVBN202 transgenic mouse. J Immunol.187(2):708-17, 2011 PMID: 21670315