Cellular and biochemical analysis of immunological suppression in tumor-bearing hosts
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
Immunology
Recommended Citation
Levey, Daniel Lewis, "Cellular and biochemical analysis of immunological suppression in tumor-bearing hosts" (1998). ETD Collection for Fordham University. AAI9816345.
https://research.library.fordham.edu/dissertations/AAI9816345
