Hussein F. Aqbi

Tumor immunoediting consisting of three phases of elimination, equilibrium or dormancy, and escape has been supported by preclinical and clinical data. A comprehensive understanding of the molecular mechanisms by which antitumor immune responses regulate these three phases are important for developing highly tailored immunotherapeutics that can control cancer. To this end, IFN-γ produced by Th1 cells, cytotoxic T cells, NK cells, and NKT cells is a pleiotropic cytokine that is involved in all three phases of tumor immunoediting, as well as during inflammation-mediated tumorigenesis processes. This essay presents a review of literature and suggests that overcoming tumor escape is feasible by driving tumor cells into a state of quiescent but not indolent dormancy in order for IFN-γ-producing tumor-specific T cells to prevent tumor relapse.

// Hussein F. Aqbi 1 , Liliya Tyutyunyk-Massey 2 , Rebecca C. Keim 1, 3 , Savannah E. Butler 1, 3 , Theresa Thekkudan 2 , Supriya Joshi 4 , Timothy M. Smith 1 , Dipankar Bandyopadhyay 3, 5 , Michael O. Idowu 3, 6 , Harry D. Bear 3, 7 , Kyle K. Payne 8 , David A. Gewirtz 2, 3 and Masoud H. Manjili 1, 3, 6, 9 1 Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA 2 Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA 3 Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA 4 Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA 5 Department of Biostatistics, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA 6 Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA 7 Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA 8 Department of Immunology, Moffitt Cancer Center, Tampa, 33612, FL, USA 9 VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA Correspondence to: David A. Gewirtz, email: david.gewirtz@vcuhealth.org Masoud H. Manjili, email: masoud.manjili@vcuhealth.org Keywords: breast cancer; autophagy; tumor dormancy; tumor escape and relapse; cancer immunotherapy Received: March 15, 2018      Accepted: April 07, 2018      Published: April 24, 2018 ABSTRACT Breast cancer patients who initially respond to cancer therapies often succumb to distant recurrence of the disease. It is not clear why people with the same type of breast cancer respond to treatments differently; some escape from dormancy and relapse earlier than others. In addition, some tumor clones respond to immunotherapy while others do not. We investigated how autophagy plays a role in accelerating or delaying recurrence of neu-overexpressing mouse mammary carcinoma (MMC) following adriamycin (ADR) treatment, and in affecting response to immunotherapy. We explored two strategies: 1) transient blockade of autophagy with chloroquine (CQ), which blocks fusion of autophagosomes and lysosomes during ADR treatment, and 2) permanent inhibition of autophagy by a stable knockdown of ATG5 (ATG5 KD ), which inhibits the formation of autophagosomes in MMC during and after ADR treatment. We found that while CQ prolonged tumor dormancy, but that stable knockdown of autophagy resulted in early escape from dormancy and recurrence. Interestingly, ATG5 KD MMC contained an increased frequency of ADR-induced polyploid-like cells and rendered MMC resistant to immunotherapy. On the other hand, a transient blockade of autophagy did not affect the sensitivity of MMC to immunotherapy. Our observations suggest that while chemotherapy-induced autophagy may facilitate tumor relapse, cell-intrinsic autophagy delays tumor relapse, in part, by inhibiting the formation of polyploid-like tumor dormancy.

To discover distinct immune responses promoting or inhibiting hepatocellular carcinoma (HCC), we perform a three-dimensional analysis of the immune cells, correlating immune cell types, interactions, and changes over time in an animal model displaying gender disparity in nonalcoholic fatty liver disease (NAFLD)-associated HCC. In response to a Western diet (WD), animals mount acute and chronic patterns of inflammatory cytokines, respectively. Tumor progression in males and females is associated with a predominant CD8+ > CD4+, Th1 > Th17 > Th2, NKT > NK, M1 > M2 pattern in the liver. A complete rescue of females from HCC is associated with an equilibrium Th1 = Th17 = Th2, NKT = NK, M1 = M2 pattern, while a partial rescue of males from HCC is associated with an equilibrium CD8+ = CD4+, NKT = NK and a semi-equilibrium Th1 = Th17 > Th2 but a sustained M1 > M2 pattern in the liver. Our data suggest that immunological pattern-recognition can explain immunobiology of HCC and guide immune modulatory interventions for the treatment of HCC in a gender-specific manner.

Abstract Background Although breast cancer mortality is a result of distant recurrences associated with the establishment of tumor dormancy, current clinical practice guidelines recommend a wait and watch approach for tumor recurrences. This is because of our limited understanding of tumor dormancy and insufficient evidence in support of immunological control of tumor dormancy. Methods We used FVBN202 transgenic mice expressing rat neu oncogene in the mammary glands, and their parental FVB strain lacking neu expression. These models allowed the detection of tumor dormancy at distant sites using the rat neu protein as a tumor marker. We also used Ki67 for the detection of the indolent and quiescent types of tumor dormancy. Multicolor flow cytometry was used to detect dormant tumor cells and T cell subsets. Co-culture studies were performed to determine the role of T cells in preventing regrowth of dormant cells. Results We demonstrated that dormant tumor cells were present at the site of primary breast cancer and at distant sites in the lungs and in the liver very early in the course of early stage breast cancer when no distant metastasis was evident. Dormant tumor cells were characterized as neu expressing Ki67 − and Ki67 low fractions associated with the induction of local immune responses predominated by CD4+ and CD8+ T effector cell subsets. The presence of neu-autoreactive T cells from FVBN202 mice only prevented regrowth of dormant cells. On the other hand, presence of neu-alloreactive anti-tumor T cells in FVB mice prior to tumor challenge resulted in the protection of mice from the dissemination of dormant tumor cells to distant organs. Conclusion Our results suggest that immunotherapeutic targeting of semi-allogeneic mutant neoantigens during tumor dormancy might prevent distant recurrence of the disease.

BACKGROUND AND AIMS: Chronic diseases such as nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) are associated with chronic inflammation. However, controversial reports as to the key cytokines involved in the process of chronic inflammation hinder development of targeted therapies for patients. This is because, chronic inflammatory process cannot be fully understood by studying the mechanisms of the disease in a short-term or isolated fashion. Understanding of the trend of inflammatory cytokines through longitudinal studies could provide a profound insight into the process of disease progression. METHODS: We performed a longitudinal analysis of inflammatory cytokines/chemokines and faecal microbiome dysbiosis associated with the diet-induced progression of NAFLD to HCC in diet-induced animal model of NAFLD comparing males and females, since males show a higher incidence of these diseases than females do. RESULTS: Longitudinal analyses revealed that a transient and timely increase in LIF and TMIP1 was associated with the inhibition of the progression of NAFLD to HCC in females. On the other hand, chronically increasing trends in CCL12, CCL17, CXCL9 and LIX/CXCL5 were associated with the promotion of the progression of NAFLD to HCC in males. CONCLUSIONS: We provided empirical evidence that a methodological shift from snapshot observations to longitudinal data collection and analysis can provide a better understanding of chronic liver diseases.