Khashayarsha Khazaie, PhD, DSc Associate Professor Medicine Understanding Immune Evasion and Inflammation in Cancer Curricula: Cancer Biology Immunology and Microbial Pathogenesis E-mail:   khazaie@northwestern.edu

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Cancer is a systemic disease. It requires an intricate interaction between the oncogenically mutated cell and the universe of immune cells reacting to the tumor, each stimulating and modifying the other to the detriment or benefit of the host with the former dominating progressive malignant disease. We are using animal models of cancer and specimens from cancer patients to understand the immune pathology of cancer. This experience allows us to design therapeutic interventions that target the tumor and it’s microenvironment.

Protective Immune Responses in Cancer
Recent clinical studies have documented ongoing anti-tumor immune responses in cancer patients. We postulate that the often long latencies between surgical removal of primary tumor and cancer recurrence is largely due to control of minimal residual disease by such naturally protective immune responses, and propose to employ them to eradicate disseminated tumor cells and prevent malignant disease. The vaccination strategy uses long peptides carefully characterized to activate tumor specific memory T-cells that are protective while avoiding pathogenic immune cells (Figure 1). Vaccinated patients will be monitored individually to help us understand not only the efficacy of the vaccines but to discover mechanisms and improve therapeutic strategies. This work is in close collaboration with the Laboratory of Dr. Philipp Beckhove at the German Cancer Research Center and Surgical Oncology, Hematology Oncology and Gastroenterology of Northwestern University and Robert H. Lurie Comprehensive Cancer Center.

Pro-tumor Immune Responses
A major obstacle for immune therapy of cancer is the presence of T-regulatory cells and their expansion in cancer patients. These cells normally protect against autoimmunity but in cancer they protect the tumor from host immune surveillance. Treg are not just immune suppressive cells. In cancer and in autoimmune disease Treg readily convert into pathogenic cells that feed tumors and destroy healthy tissue. The preferential access of Treg over other T-cell types to the tumor microenvironment and their pro-inflammatory functions renders these cells particularly dangerous in cancer. Inflammatory cells including mast cells infiltrate and nurture the tumor with factors that facilitate growth and invasion. These are normally suppressed by Tregs but in cancer diversion of Treg to a pro-inflammatory phenotype helps to promote their expansion and activity. Successful immune therapy needs to consider the contribution of Treg to the shaping of the tumor microenvironment. We hypothesize that targeting the cross talk between Treg and other pro-inflammatory cells in cancer will help to shift the immune response from pathogenic to protective functions and eradicate cancer. Our current work focuses on colorectal, pancreatic and breast cancer. This work is in collaboration with Surgical Oncology, Hematology Oncology and Gastroenterology of Northwestern University and Robert H. Lurie Comprehensive Cancer Center.

Imaging of Cancer Associated Inflammation
Tumor infiltrating mast cells, myeloid derived suppressor cells, and macrophages are essential for tumor growth and progression. These cells are responsible for focally elevated levels of proteases of the Cathepsin family in the tumor microenvironment. We have shown that Cathepsin activity is a critical component of progressive tumors. Imaging this activity provides a new paradigm for diagnosis of cancer based on visual detection of biological activity rather than structural abnormalities. To this aim we use novel Cathepsin inducible near infra-red fluorescent probes to image dysplasia in mouse models of colorectal cancer and ulcerative colitis. The probes are either substrates or suicide inhibitors and fluoresce upon cleavage or binding to Cathepsins. Specimens from patients are used to confirm our findings and relate to human disease. The technology has particular application to intravital and endoscopic detection of microscopic lesions. In collaboration with colleagues at the Division of Gastroenterology of the Northwestern Feinberg School of Medicine and with Olympus Japan we are working to develop and translate to the clinic the early endoscopic detection and monitoring of cancer based on visualization of biologic activity in the tumor stroma. This work is in collaboration with the laboratories of Dr. Ralph Weissleder (Harvard Medical School), Dr. Mathew Bogyo (Standford University), Olympus Japan, and Visen Biomedicals MA.

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