Khashayarsha Khazaie, Ph.D.

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SUMMARY

Khashayarsha Khazaie (Khash), Ph.D., D.Sc., conducts basic and translational research in cancer immunology and inflammation. This research is primarily focused on the interface of tumor, microbiota, and immunity. Of special interest are mechanisms by which the immune system is subverted in cancer to help promote tumor growth and dissemination. Dr. Khazaie and his team focus particularly on cancers of the small bowel and colon, and gynecological cancers.

The laboratory also investigates immunity in metastatic disease. Basic research is conducted to understand differences in immune response to metastatic endometrial cancer versus disseminated ectopic endometrium in endometriosis. In a separate study, the laboratory partners with Biomed Valley to develop microbial vaccines for the treatment of advanced metastatic disease.

Dr. Khazaie is dedicated to ensuring continually high-quality patient care through the education of current and future physicians and scientists and carries out various teaching activities in the field of immunology and cancer biology.

Focus areas

• Regulatory T cells and microbiota in gastrointestinal malignancies. The laboratory has longstanding interest in regulatory T cells (Tregs) and their role in cancer. Dr. Khazaie and his team contributed to the earliest reports of antigen specific and TGF-β dependent Treg suppression of CD8⁺ T cells in mouse models of cancer, and the distinct repertoire of Treg cognate antigens relative to that of conventional CD4⁺ T cells in colorectal cancer (CRC). A major interest is molecular mechanisms of Treg plasticity in cancer, and the role of cell intrinsic and extrinsic factors. Expression of RORγt⁺ normally distinguishing a subset of Tregs that are generated in the gut upon activation of conventional CD4⁺ T cells by microbial antigens and metabolites. Through secretion of IL-10 these cells maintain gut homeostasis by suppressing pathobiont-induced inflammation. The reversal of this function in CRC and inflammatory bowel diseases is an underlying cause of tumor pathogenic inflammation, which is characteristically T cell suppressive and tumor promoting. Related cell intrinsic mechanisms under study include epigenetic reprograming of Treg and T-helper cell functions by β-catenin and its DNA binding partner Tcf-1. Cell extrinsic mechanisms under study include opportunistic pathogens related to the oral microbiota, bacterial metabolites and bacterial networks.
  • Short Term Goals: Define driver-virulent bacteria, microbial networks, epigenetic mechanisms, and nuclear factors and their molecular interactions that modulate Treg and T-helper cell expansion and functions in CRC.
  • Long Term Goals: Treg and microbial targeted therapeutics.
• Innate immunity in gastrointestinal malignancies. In a series of publications, the lab reported that mast cells contribute to tumor growth in mouse models of spontaneous polyposis. Distinct types of mast cells were identified that expand in a tumor stage dependent manner and contribute to the initiation and progression of tumors in mice. Mast cell interactions with Tregs contributed to Treg dysfunction. Mast cells co-localized with innate lymphoid cells (ILCs) and promoted pathogenic inflammation in polyposis. Depletion of mast cells or genetic ablation of mast cell proteases attenuated polyposis.
  • Short Term Goals: Ongoing studies aim to discover molecular mechanisms of mast cell plasticity in cancer, mechanisms through which they promote tumor growth, and relevance to cancer in humans.
  • Long Term Goals: To define mechanisms of pathogenic inflammation produced by tissue sentinel innate immune cells in gastrointestinal malignancies.
• Circadian rhythm and cancer immunity. The laboratory is interested in how molecular pathways that control circadian rhythms influence immunity in cancer. Earlier studies implicated abnormal feeding habits in promotion of CRC in mouse models, pointing to pathogenic inflammation as potential mechanism. Ongoing studies focus on core clock genes including CLOCK and Bmal in altering Treg functions in CRC. Epigenetic and gene expression changes caused by disruption of core clock genes are studied in the context of pathogenic TH17 inflammation in hereditary and sporadic CRC.
  • Short Term Goals: To establish the role of core clock genes in protective versus pathogenic immunity in cancer.
  • Long Term Goals: Novel cancer prevention and treatment strategies focused on the circadian genes.
• Fibrosis, endometriosis and endometrial cancer metastasis. Fibrosis is a common complication associated with endometriosis and is a common characteristic that hinders anti-tumor immunity. The lab has used mouse modeling of endometriosis to better understand the genetic and immunologic basis of the fibrotic reactions in this disease. Endometriosis also bears similarities to metastatic endometrial cancer by dissemination of the ectopic endometrium to distant organs. Multiplex in situ immunostaining is used for side-by-side comparison of the microenvironments of the ectopic endometrium and endometrial cancer metastasis in the gut. These studies reveal how the disseminated malignant versus non-malignant endometrial cells shape host immunity to the lesions in distant organs.
  • Short Term Goals: To gain insight into the genetic mechanisms of fibrosis in endometriosis and learn how malignant versus nonmalignant endometrial cells shape their microenvironment in distant sites and alter immunity to promote the respective pathologies.
  • Long Term Goals: Immunotherapy of endometriosis and endometrial cancer.
• Microbial-based cancer vaccines. The lab performs correlative studies of ongoing clinical trials (NCT01924689; NCT03435952) with a novel bacterial vaccine for treatment of therapy refractory metastatic cancer patients. The trials are collaborations with Biomed Valley Discoveries and MD Anderson Cancer Center in Texas and are sponsored by Biomed Valley Discoveries.
  • Short Term Goals: To demonstrate that intratumor germination of Clostridium Novyi-NT spore produces immunogenic tumor cell death and stimulates systemic tumor antigen specific T cell responses and therapeutic benefits in patients with treatment-refractory solid tumor malignancies.
  • Long Term Goals: To evaluate the therapeutic potential of combining bacterial vaccines with immune checkpoint inhibition and to understand the immunology of tumor rejection.

Significance to patient care

The ultimate goal of Dr. Khazaie's studies is to achieve better outcomes for cancer patients and to improve health span through manipulation of the immune system.

Professional highlights

• Director, Federation of Clinical Immunology Societies, Mayo Clinic Center of Excellence, 2018- present
• Associate editor, Journal for ImmunoTherapy of Cancer, 2013-present
• Editorial board, Cancer Immunology Research journal, 2012-present
• Associate editor, Tumor Immunity, Frontiers of Immunology and Frontiers in Oncology, 2011-present
• Visiting Professor at the University of Regensburg, Germany, July 2016
• Visiting Professor at the Université Paris - Est Creteil (UPEC), France, June 2016
• Associate Professor, Northwestern University, Chicago, 2007-2011
• Assistant Professor, MGH, Harvard Medical School, Boston, 2003-2007
• Instructor, Dana Farber Cancer Institute, Harvard Medical School, Boston, 1999-2003
• Visiting Professor at Université Paris V, René Descartes, Paris, France, 1998-1999
• Habilitation á diriger des recherches (HDR), Faculty of Medicine Necker, University of Paris, France, 1988