Extracellular stimuli may influence the M1/M2 phenotypic polarization of macrophages. We examined M1/M2 biomarkers, phagocytic activity, and tumoricidal activity in RAW 264.7 mouse macrophages. Macrophages were treated with conditioned media (CM) from 4T1 breast cancer cells, curcumin, 22-oxacalcitriol, LPS, or a combination of the previously listed. Arginase activity, a M2 phenotypic biomarker, was upregulated by the treatment of macrophages with conditioned media. Curcumin, 22- oxacalcitriol, and LPS partially inhibited RAW 264.7 arginase activity in the presence of 4T1 breast cancer media. 22-oxacalcitriol increased the phagocytic ability of RAW 264.7 macrophages in the presence of M2 polarizing substances produced by the 4T1 breast cancer cells. Also, LPS increased RAW 264.7 phagocytic ability in the presence of 4T1 breast cancer CM. This study looked at the potential substances that would possibly reverse the M2 tumor promoting macrophage phenotype seen in the breast cancer tumor environment. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2017. / FAU Electronic Theses and Dissertations Collection

Bibliography: leaves 218-251.

A foundation for the control of tumors is presented, based upon the formulation of a realistic, knowledge-based mathematical model of the interaction between tumor cells and the immune system. The parametric control variables relevant to the latest experimental data, e.g., the sigmoidal dose-response relationship and Michaelis-Menten dynamics, are also considered. The model consists of 12 states, each composed of first-order, nonlinear differential equations based on cellular kinetics and each of which can be modeled bilinearly. In recent years a great deal of clinical progress has been achieved in the use of optimal controls to improve cancer therapy patient care. For this study, a cancer immunotherapy problem is investigated in which the aim is to minimize the tumor burden at the end of the treatment period, while penalizing excessive administration of interleukin-2 as a limit of toxicity. The optimal solution developed for this investigation is a mixture of an initially large dose of interleukin-2, followed by a gradually decreased dosage and a continuing infusion to maintain the tumor cell population at its allowable limit. Sensitivity analysis is applied to an investigation of the influences of system parameters. It has been found that the immune system is influenced greatly by several parameters such as macrophage level, tumor killing rate, tumor growth rate, and IL-2 level. The simulation results suggest that parametric control variables are important in the destruction of tumors and that the application of exacerbation theory is a good method of tumor control. / Graduation date: 1991

Prostaglandin E2 (PGE2) is an immunosuppressive factor secreted by the murine Lewis lung carcinoma (LLC). This factor can help to insure the survival of a tumor by suppressing the functions of lymphocytes and macrophages in their defense against tumors.Four weekly assays of macrophage tumoristatic activity from tumor-bearing mice were performed during the course of tumor development. Macrophages from the peritoneal cavity were cultured with LLC cells and after 48 hours the LLC growth was measured.The results of this study showed that macrophages from tumorbearing mice were suppressed in their ability to halt LLC growth in vitro. This suppression could be prevented by the use of indomethacin, a prostaglandin synthesis inhibitor. Indomethacin administration to tumor-free mice also enhanced their macrophage tumoristatic activities suggesting that the tumor was not the exclusive source of prostaglandin which suppressed anti-tumor immunity. Finally, indomethacin-fed tumor-bearing mice had smaller tumors than did mice not fed indomethacin.Ball State UniversityMuncie, IN 47306

The immune regulatory abilities of alveolar macrophages from C57B1/6 mice bearing a metastatic variant of Lewis lung carcinoma were determined. During early stages of tumor development, or before tumors metastasized to the lungs, alveolar macrophages did not affect or slightly enhanced T-lymphocyte proliferation; as tumor growth progressed, or following tumor metastasis, alveolar macrophages suppressed the T-cell response. Macrophage suppressor activity was probably not mediated by their production of PGE, since macrophages of tumor-bearing mice secreted less 2 PGE than did macrophages of normal mice. Normal alveolar 2 macrophages or macrophages preincubated in tumor cell supernatant for a short period stimulated T-cell blastogenesis and secreted PGE during in vitro culture. However, with 2 longer exposure to tumor cell supernatant, alveolar macrophages lost the capacity to augment T-cell proliferation and secreted less PGE 2.Ball State UniversityMuncie, IN 47306

Bibliography: leaves 218-251 / xviii, [ca. 100] leaves : ill ; 31 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Microbiology and Immunology, 1983

No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / Tolerance mechanisms, which collectively work to prevent autoimmunity, play a key role in suppressing the adaptive immune response to tumor antigens. This phenomenon is attributed to the extensive overlap of tumor associated antigens with self peptides. We studied immune tolerance to tumor antigen TRP-1, a melanoma associated glycoprotein. Vaccination of Wild type (WT) and TRP-1 deficient (Bw) mice with TRP-1 antigen highlighted the substantial effect of tolerance on the T cell response: in the Bw population a log-fold differential was observed with greater clonal numbers and higher intensity of cytokine release from the antigen specific CD4+ T cell population. Additionally, TRP-1-reactive T cells derived from Bw mice demonstrated significantly more efficacious tumor treatment ability than WT donor cells when adoptively transferred into recipients challenged with B16 melanoma. Furthermore, donor Bw T cells were so potent as to overcome suppression by endogenous Tregs in mediating their effect. Probing for a tolerance mechanism, we isolated medullary thymic epithelial cells (mTECs) from WT mice and found that they promiscuously express TRP-1. Unexpectedly, TRP-1 expression in mTECs was found to occur independently of the prominent Autoimmune Regulator (Aire) transcription factor as well as the melanocyte specific transcription factor, mMitf. Our most recent data suggests that thymic dendritic cells may also express copies of the TRP-1 transcript. Future transplant studies will test whether mTECs or thymic dendritic cells directly tolerize TRP-1 specific T cells. Overall, these findings highlight the relevance of central tolerance to cancer immunology and compel further investigation of its mechanistic impact on the development of tumor-reactive T cells.bb

Mining the human genome for therapeutic target(s) discovery promises novel outcome. Over half of the proteins in the human genome however, remain uncharacterized. These proteins offer a potential for new target(s) discovery for diverse diseases. Additional targets for cancer diagnosis and therapy are urgently needed to help move away from the cytotoxic era to a targeted therapy approach. Bioinformatics and proteomics approaches can be used to characterize novel sequences in the genome database to infer putative function. The hypothesis that the amino acid motifs and proteins domains of the uncharacterized proteins can be used as a starting point to predict putative function of these proteins provided the framework for the research discussed in this dissertation. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2015. / FAU Electronic Theses and Dissertations Collection

[Truncated abstract] The design of effective immunotherapies, using tumour antigens to stimulate a functional effector cytotoxic T cell (CTL) response in a tumour bearing host, requires an understanding of the 'real time' in vivo relationship between the host immune system and antigens expressed by the developing tumour. However, effector function of endogenous anti-tumour CTLs generated during tumour progression has largely been assessed by indirect ex vivo assays and often focused on a single antigen. Therefore, studies in this thesis evaluated the endogenous in vivo CTL response to multiple tumour antigenic epitopes in murine tumour models using Lewis lung carcinoma cells transfected with ovalbumin (an antigen that contains several intra-molecular MHC class I epitopes with a defined hierarchy) or a polyepitope (that contains a string of immunodominant MHC class I epitopes). Potent effector CTLs were generated to multiple dominant tumour antigenic epioptes early in tumour progression. However, in general, these CTL effectors only transiently retarded tumour growth, and at the later time points of tumour growth they were no longer generated in tumour draining lymph nodes. This coincided with diminished tumour antigen presentation in the same nodes which was found to be due to antigen loss. In both models antigen loss was the result of two processes; immuno-editing of the tumour by the host immune response and genetic instability resulting in antigen loss variants that could evade immune surveillance. A third model was generated that maintained low level tumour antigen expression throughout tumour progression. ... The impact of pre-existing endogenous dominant-epitope specific CTLs on tumour expressing the same epitope was also assessed, and resulted in a reduced tumour incidence and a CTL response restricted to a single antigen of the same MHC allele. Finally, the effects of two different immunotherapy regimens were examined. Intratumoural IL-2 treatment enhanced pre-existing CTL responses to the dominant epitopes leading to tumour regression. In addition, use of a multiple peptide vaccination regimen that avoided T cells competing for peptide-MHC complexes on APC was far more likely to be effective than one that did not. These results demonstrate that immunotherapies targeting tumours that express several dominant neo antigenic epitopes can be effective. The caveat for this approach is that it will only be effective in tumours that have generated an endogenous CTL response and must be used before antigen loss variants emerge.