Cellular and biochemical analysis of immunological suppression in tumor-bearing hosts

Daniel Lewis Levey, Fordham University

Abstract

Loss of T cell-associated signal transduction molecules has recently been implicated in immune suppression in tumor-bearing hosts. In the first part of the dissertation, the expression of such proteins and the functional status of T cells were extensively examined in a large number of tumor-bearing mice, analyzed individually. Splenic T cells from tumor-bearing mice were isolated and characterized with respect to (i) levels of three tyrosine kinases, p56$\rm\sp{lck},\ p59\sp{fyn}$ and ZAP-70, (ii) expression of CD3$\zeta$, (iii) alloreactive responses, and (iv) antigen-specific responses. Contrary to recent reports, T cells from tumor-bearing mice were observed to express normal levels of lck, fyn, ZAP-70 and CD3$\zeta$. Further, T cells showed healthy alloreactive and antigen-specific responses until $\sim$3 weeks post-tumor challenge, when the tumors constituted $\sim$20% of the body weight. Alterations with respect to some parameters were observed only in mice which had been bearing larger tumors for a considerably longer period. Altogether, these results indicate that alterations in T cell signal transduction molecules do not account for the profound tumor-specific suppression observed during tumor growth. The evidence for these alterations in the context of the tumor-specificity of immunological un-responsiveness in tumor-bearing hosts is critically examined and discussed.^ In part II of the dissertation, immunosuppressive characteristics of tumor cells are described, with particular emphasis on the Meth A sarcoma. Although in vivo evidence demonstrates that Meth A cells are immunogenic and can elicit tumor regression, it has not been possible to generate Meth A-specific CTLs in vitro. Experiments were designed to address this apparent conundrum. It is demonstrated that Meth A cells do not secrete TGF-$\beta$ or other immunosuppressive soluble factors; rather, the suppressive activity is dependent on cell-cell contact. The suppressive activity is preserved within Meth A whole membrane preparations; the activity is susceptible to lipase digestion but not to proteolytic digestion. The suppressive activity of Meth A tumor cells and two other methylcholanthrene-induced tumors is reversible, since CTLs recover lytic ability if they are separated from tumor cells. ^

Subject Area

Health Sciences, Immunology

Recommended Citation

Daniel Lewis Levey, "Cellular and biochemical analysis of immunological suppression in tumor-bearing hosts" (January 1, 1998). ETD Collection for Fordham University. Paper AAI9816345.
http://fordham.bepress.com/dissertations/AAI9816345

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