Research projects

Immunotherapy of cancer dormancy

Disseminated dormant 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. The objective of this project is to identify molecular and cellular events that establish tumor dormancy after cancer therapies, and those that lead to disease recurrences. We have reported that dormant tumor cells become resistant to chemotherapy and radiation therapy primarily because of becoming 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. Currently, we are developing neoadjuvant therapies using small molecules that target dormant tumor cell survival pathways, as well as personalized immunotherapies for targeting tumor dormancy-associated neoantigens for the prevention of metastatic recurrences of cancer.

 

• Aqbi HF, Coleman C, Zarei M, Manjili SH, Graham L, Koblinski J, Guo C, Xie Y, Gurulu G, Bear HD, Wang XY, Manjili MH. Local and distant tumor dormancy during early-stage breast cancer are associated with the predominance of infiltrating T effector subsets. Br Cancer Res. 22(1):116, 2020  PMID: 33115528
• Manjili MH. Tumor dormancy and relapse: from a natural by-product of evolution to a disease state. Cancer Res77 (10) 2564-2569, 2017   PMID: 28507050

 

Discovery of immunological patterns associated with the progression or inhibition of diet-induced fatty liver disease and hepatocellular carcinoma

Molecular interactions and rearrangements can create distinct patterns, which cannot be fully understood by taking a reductionist approach. For instance, different sequential patterns of only 4 nucleotides in the double-helix DNA create different functions which cannot be understood by exploring a cause-and-effect relationship among the nucleotides. In nature, drinking water (H₂O) or toxic hydrogen peroxide (H₂O₂) and hydroxyl radical (HO) are made up of different proportions of hydrogen and oxygen, producing different molecular patterns and creating with new properties above and beyond the property of their components. Again, property of water cannot be understood by breaking it down to hydrogen and oxygen. Similarly, different proportions of lymphocyte subsets could create new collective functions emerging from their interactions, which are independent from the function of their constituents. Therefore, immunological pattern recognition of the diseased microenvironment could provide us with a better understanding of the immune responses. To this end, we have reported that an equilibrium Th1=Th17=Th2, NKT=NK, M1=M2 pattern, semi-equilibrium Th1=Th17>Th2, CD8⁺=CD4⁺, NKT=NK pattern, or predominant CD8⁺>CD4⁺, Th1>Th17>Th2, NKT>NK, M1>M2 pattern could each result in different clinical outcomes from complete tumor inhibition, partial tumor inhibition to tumor progression, perhaps, because of generating distinctively collective functions, independent from their cellular components.

 

• Mirshahi^, F, Aqbi HF, Isbell M, Manjili SH, Guo C, Saneshaw M, Bandyopadhyay D, Dozmorov M, Khosla A, Wack K, Carrasco-Zevallos OM, Idowu MO, Wang XY, Sanyal AJ, Manjili MH. Distinct hepatic immunological patterns are associated with the progression or inhibition of hepatocellular carcinoma. Cell Reports38(9):110454, 2022      PMID: 35235789
• Manjili MH, Khazaie K. Pattern recognition of tumor dormancy and relapse beyond cell-intrinsic and cell-extrinsic pathways.  Seminars in Cancer Biol78: 1-4, 2022    PMID: 34990835

 

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 or allergy. We have proposed the adaptation model of immunity based on which signal III or communication signaling determines the outcome of the immune response.  Signal III is orchestrated through adaptation receptors (AdRs) and adaptation ligands (AdLs). Any alterations in the expression of AdRs on target cells render them susceptible to an ongoing immune response.

According to this model, all somatic cells ubiquitously express AdRs which are linked to anti-apoptotic pathways so as to protect the host from inflammatory immune responses induced during infection or other environmental insults. Loss or downregulation of the AdRs in certain tissues is the primary cause of cellular injury. In fact, tumor escape from cancer therapies could be due to upregulation of the AdRs; similarly, alternating periods of flare-ups and remission in patients with autoimmune diseases could be due to downregulation and restoration of the AdRs, respectively. Similar mechanisms could explain a better engraftment of less matched organs from living donors compared with fully matched organs from cadaver donors, perhaps, because of the loss or downregulation of the AdRs in a cadaveric organ being more vulnerable to inflammatory immune responses. Our model can also explain pre-existing MSB-specific autoimmune responses in healthy individuals without any clinical manifestation of MS because of the retention of the AdRs.

The adaptation model of immunity also provides new understanding for central tolerance in the thymus, proposing that the goal of negative selection is not to eliminate self-reactive T cells, rather it is to eliminate faulty T cells that undergo apoptosis upon receiving a co-stimulatory signal from DCs. Therefore, any escape from negative selection would not always cause autoimmunity, rather, it would cause lymphopenia due to massive lymphocyte apoptosis, which is the case in patients with sepsis due to an injured thymus and defective negative selection.  

• Manjili MH. A theoretical basis for the efficacy of cancer immunotherapy and immunogenic tumor dormancy: The adaptation model of immunity. Adv Cancer Res 137:17-36, 2018  PMID: 29405975
• Manjili MH. The adaptation model of immunity. Immunotherapy 6(1):59-70, 2014. PMID: 24341885