Strategies for exploiting the immune system to achieve prevention and improve therapy of cancer
Hamilton, Duane Howard
It has steadily become more recognized that even patients with progressively growing tumors are often mounting substantial immune responses against their tumor. The reasons why this immunity is unable to control the outgrowth of the tumor must be understood if we are to develop immunotherapeutic and preventative strategies against cancer. Experimental observations since the 1960s have suggested that cellular immunity generated against tumor antigens is protective, while some studies have led me to believe that humoral immunity may be associated with disease progression. This possibility has led me to test the hypothesis that the cause of immune failure is immune-deviation.The experimental system I chose employs the P815 mastocytoma and L5178Y lymphoma tumors, both of which are of DBA origin. I have demonstrated that primary resistance to tumors correlates with Th1 responses, while primary progressive tumor growth is associated with a mixed Th1/Th2 immune response generated against tumor antigens. Such correlates were defined directly by assessing tumor-dependent cytokine secretion by T cells, and indirectly by assessing the relative abundance of tumor-specific IgG2a and IgG1 antibodies by western blot and enzyme-linked immunoassays. Moreover, I have demonstrated, utilizing these assays, that low doses of gamma irradiation, which have previously been shown to induce immune-mediated regression of established tumors, is associated with a phenotypic ‘switch’ in the anti-tumor immune response from a mixed Th1/Th2 to a predominant Th1 response. The simplicity and reliability of using IgG isotypes to indirectly assess the Th1/Th2 nature of the anti-tumor immune response gives me hope that this work, in the long run, will result in a new way of guiding immunotherapy to effectively treat cancer.
DegreeDoctor of Philosophy (Ph.D.)
DepartmentMicrobiology and Immunology
ProgramMicrobiology and Immunology
SupervisorBretscher, Peter A.
CommitteeHoward, S. Peter; Havele, Calliopi; DeCoteau, John; Bull, Harold