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Immune Blockade Therapy in Metastatic Osteosarcoma

Description

Since Metastatic Osteosarcoma is unresponsive to most of the current standards of care currently available, and yields a survival rate of 20%, it is pertinent that novel approaches to treating it be undertaken in scientific research. Past studies in our lab have used a The Immune Blockade Therapy, utilizing α-CTLA-4 and α-PD-L1 to treat mice with metastatic osteosarcoma; this resulted in 60% of mice achieving disease-free survival and protective immunity against metastatic osteosarcoma. 12 We originally wanted to see if the survival rate could be boosted by pairing the immune blockade therapy with another current, standard of care, radiation. We had found that there were certain, key features to experimental design that had to be maintained and explored further in order to raise survival rates, ultimately with the goal of reestablishing the 60% survival rate seen in mice treated with the immune blockade therapy. Our results show that mice with mature immune systems, which develop by 6-8 weeks, should be used in experiments testing an immune blockade, or other forms of immunotherapy, as they are capable of properly responding to treatment. Treatment as early as one day after should be maintained in future experiments looking at the immune blockade therapy for the treatment of metastatic osteosarcoma in mice. The immune blockade therapy, using α-PD-L1 and α-CTLA-4, seems to work synergistically with radiation, a current standard of care. The combination of these therapies could potentially boost the 60% survival rate, as previously seen in mice treated with α-PD-L1 and α-CTLA-4, to a higher percent by means of reducing tumor burden and prolonging length of life in metastatic osteosarcoma.

ContributorsLabban, Nicole (Author) / Blattman, Joseph (Thesis director) / Appel, Nicole (Committee member) / Barrett, The Honors College (Contributor)

Created2017-05

Characterizing Unconventional T Cells in Lung Metastases of Metastatic Osteosarcoma and The Impact of Making Immunology More Engaging for Undergraduate Students

Description

IOsteosarcoma is the most common bone cancer and typically affects patients in the second decade of life. Current treatment methods have not proven effective for treating reoccurring or metastatic osteosarcoma (mOS) given the 5-year survival rate of 15-30%. Previous work showed that using the immune system to fight the cancer significantly improved survival of mOS in mice, but approximately 40-50% of treated mice still succumbed to disease. To further improve immunotherapy, I analyzed immune cells in the tumor bed and observed high numbers of a rare T cell subtype: CD4hiCD8αhi, or double positive (DP), T cells. While previous literature found mature DP T cells in chronic diseases, the associations and functions of this rare T cell subtype varied between studies and were unknown for mOS. Controlling for age, chronicity of disease, and environmental exposure, I found DP T cells composed a higher percentage of T cells in the cancer as tumor burden increased. I then tested whether the DP cells were pro- or anti-tumor. I found that DP cells produced the cytokines IFNγ and IL-2 when exhaustion was overcome. They also expressed FasL for cytotoxic function, although the target is unknown. These findings suggest DP T cells have multifunctionality, which could be advantageous when responding to high antigen load. II Course-based undergraduate research experiences (CUREs) offer students opportunities to engage in critical thinking and problem solving. However, quantitating the impact that incorporating research into undergraduate courses has on student learning has been difficult since most CUREs lack a comparable traditional course as a control. Because the overall class structure remained unaltered when our upper division immunology course transitioned to a CURE class, we realized retrospectively that we were in a unique position to quantitate the impact of incorporating research on student performance. I then analyzed the summative assessments used to assess student learning and found that students in the CURE format class performed significantly better on quizzes, exams, and reports. There were no significant differences in academic levels, degree programs, or grade point averages, suggesting improved performance was due to increased engagement of students in research.

ContributorsAppel, Nicole (Author) / Blattman, Joseph (Thesis advisor) / Anderson, Karen (Committee member) / Lake, Douglas (Committee member) / Hingorani, Pooja (Committee member) / Arizona State University (Publisher)

Created2022

Characterizing The Effects of The Mohawk Gene on The Immune System and Response to LCMV Infection

Description

The Mohawk (mkx) gene functions as a transcriptional repressor for tendon morphogenesis during embryonic development. Previous research showed that mkx KO mice overexpressed the osteogenic gene Runx2. Runx2 plays a role in recognition and long-term immune memory. A study showed Runx2 KO mice had a significantly lower number of CD8 T cells specific to lymphocytic choriomeningitis virus (LCMV) and CD8 memory precursor T cells. To determine the direct effects of Mohawk expression on the immune system, development, acute response, and immune memory of innate, B and T cells were compared between WT and mkx KO mice after LCMV infection. Paired t-test analyses were performed between KO and WT data. We first found significantly higher numbers of granulocytes and dendritic cells in the periphery but lower numbers of B cells in the bone marrow and T cells in the thymus of KO mice. When analyzing immune response, we observed a significantly high number of activated CD8 T cells that proliferated in the KO mice in response to the infection. Next, we found no difference in cytokine production for TNF and IFNγ which shows Mohawk does not impair acute immune response. Finally, we found no significant difference between WT and KO mice in the CD8 T cells' ability to make an immune memory. In the present study, we found that, fewer immune cells continued their maturation. However, Mohawk expression did not impact their acute response or ability to become memory cells once the T cells matured and became activated. Rather, T cells specific for LCMV were present in higher numbers in mkx KO mice. Further research will study the impact Mohawk has on both B and T cell memory.

ContributorsMethuku, Varshini (Author) / Blattman, Joseph (Thesis director) / Rawls, Alan (Committee member) / Appel, Nicole (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)

Created2022-05