Regulation of Anti-Tumor Immunity and Immunotherapy Response In Colorectal Cancer

University of Minnesota Ph.D. dissertation. 2020. Major: Microbiology, Immunology and Cancer Biology. Advisor: Subbaya Subramanian. 1 computer file (PDF); 172 pages.Immune checkpoint blockade therapy (ICBT) has revolutionized the treatment and management of numerous cancers, yet a substantial proportion of colorectal cancer (CRC) patients are resistant. Most importantly, the mechanisms that cause ICBT resistance in CRC patients are mostly unclear. Both clinical and laboratory studies implied that both tumor cell-intrinsic factors and traditional cancer therapies (e.g., chemotherapy and oncogenic pathway-targeted therapy) have regulatory effects on anti-tumor immunity and ICBT efficacy. In the present thesis, we first characterized the pathological and immunological features of different pre-clinical CRC models. We reported the feasibility of using small animal endoscopy to establish mouse orthotopic colon tumors. We found that tumors grown orthotopically in the colon microenvironment develop better immune infiltration than tumors with the same genetic background growing in a subcutaneous microenvironment. These data indicated that the tissue microenvironment impacts anti-tumor immunity. Meanwhile, we observed that the endoscopy-guided cancer cell line-originated orthotopic CRC model is much more sensitive to ICBT over the subcutaneous model, making it not suitable for experiments that require ICBT-resistant tumors. This observation made us decide to use the subcutaneous tumor models, which are ICBT-resistant, for understanding cancer immunotherapy resistance. In the second section, we evaluated the impact of tumor-draining lymph nodes (TdLNs) and chemotherapy on ICBT efficacy. Specifically, we demonstrated TdLNs are critical for tumor antigen-specific T-cell response in early-stage tumors. However, TdLNs shift from an immunoreactive to an immunotolerant environment during tumor development. In mice with advanced primary tumors, TdLNs are not the major reservoir of tumor antigen-specific T cells. To evaluate the impacts of those immunotolerant TdLNs on ICBT response, we established a surgical model to mimic tumor recurrence in situ. We surgically removed the established primary tumors with or without concurrent TdLNs resection. Then, we inoculated secondary tumors, which are in the same lymphatic drainage area as the primary tumors, to mimic tumor recurrency. Notably, removing those immunotolerant TdLNs concurrently with established primary tumors did not affect the ICBT response on localized secondary tumors. In another set of experiments, we evaluated the impacts of chemotherapy (5-FU) on ICBT efficacy. We revealed that using 5-FU as induction treatment for ICBT increased tumor visibility to immune cells, decreased immunosuppressive cells in the tumor microenvironment, and limited chemotherapy-induced T-cell depletion. However, sustained chemotherapy impaired the efficacy of ICBT by suppressing the host immune system and depleting tumor-infiltrating T cells. Therefore, the sequential combination of chemotherapy with ICBT may result in a better response than the sustained chemotherapy and ICBT combination. Finally, we investigated how tumor cells regulate T-cell activation via intercellular communication based on extracellular vesicles (EVs). Specifically, we revealed that tumor cells-secreted EVs (TEVs) containing microRNA miR-424 suppressed the CD28-CD80/86 costimulatory pathway in tumor-infiltrating T cells and dendritic cells. Modified TEVs with miR-424 knocked down enhanced T-cell mediated antitumor immune response in CRC tumor models and increased the response to ICBT. Intravenous injection of modified TEVs induced tumor antigen-specific immune responses. Moreover, injections of modified TEVs boosted the ICBT efficacy in CRC models that mimic treatment-refractory late-stage disease. Collectively, the present study improves our understanding of CRC anti-tumor immune regulation and proposed novel treatment for ICBT resistant human CRC

Review of Diagnosis Technique for Equipment Faults and its Development Trend

Modern control system is becoming larger and more complicated with each passing day and the possibility of system breakdown increases with it, so people eagerly need to set up fault diagnosis system to conduct real-time monitoring and fault diagnosis for production system and take necessary measures to improve its overall reliability and maintainability. This paper states the principles and basic approaches of diagnosis technique for equipment faults, introduces development phrase of fault diagnosis technique and points out future development trend in this field

a genetic clustering algorithm using a message-based similarity measure

In this paper, a genetic clustering algorithm is described that uses a new similarity measure based message passing between data points and the candidate centers described by the chromosome. In the new algorithm, a variable-length real-value chromosome representation and a set of problem-specific evolutionary operators are used. Therefore, the proposed GA with message-based similarity (GAMS) clustering algorithm is able to automatically evolve and find the optimal number of clusters as well as proper clusters of the data set. Effectiveness of GAMS clustering algorithm is demonstrated for both artificial and real-life data set. Experiment results demonstrated that the GAMS clustering algorithm has high performance, effectiveness and flexibility. © 2011 Elsevier Ltd. All rights reserved

Acquired Resistance to Immune Checkpoint Blockade Therapies

Immune checkpoint blockade therapy (ICBT) has revolutionized the treatment and management of numerous cancers, yet a substantial proportion of patients who initially respond to ICBT subsequently develop resistance. Comprehensive genomic analysis of samples from recent clinical trials and pre-clinical investigation in mouse models of cancer provide insight into how tumors evade ICBT after an initial response to treatment. Here, we summarize our current knowledge on the development of acquired ICBT resistance, by examining the mechanisms related to tumor-intrinsic properties, T-cell function, and tumor-immune cell interactions. We discuss current and future management of ICBT resistance, and consider crucial questions remaining in this field of acquired resistance to immune checkpoint blockade therapies