Marvin Rubenstein

Leukocytic Subset Distributions of Spleen Cells Obtained from Rats Bearing Variants of the Dunning Prostatic Adenocarcinoma

Employing monoclonal antibodies, the relative frequencies of mononuclear cell types found in spleen cell populations were compared between rats bearing variants of the Dunning prostate adenocarcinoma and a series of non-tumor bearing control animals. The identification and quantitation of such subsets greatly expands our knowledge of immune status and function. The results indicate that the spleen cell populations from animals bearing either the Dunning R3327-H, G or MAT-LyLu sublines have significant decreases in their helper T cell/suppressor T cell ratios when comparisons are made to cells obtained from non-tumor bearing animals. In addition decreases in total T cell content and increases in splenic monocytes were noted. It appears that most of these deviations are the result of general Dunning tumor presence, rather than due to any particular subline characteristic. These changes may be analogous to similar alterations reported in the peripheral blood of humans bearing Stage D prostatic cancer, suggesting that the Dunning tumor may provide an appropriate model for evaluating interactions between the immune response, the tumor and therapy.

Efficacy of immunopriming prior to isolation of tumor infiltrating lymphocytes for use in adoptive immunotherapy.

Adoptive immunotherapy is dependent upon the leukocytic subsets isolated as tumor infiltrating lymphocytes (TIL) prior to in vitro expansion with interleukin-2. To favorably influence T-cell subset representation in TIL the efficacy of bacillus Calmette Guerin (BCG) and cyclophosphamide (CTX) priming was evaluated in rats bearing Dunning R3327-AT prostatic tumors. When assessed by immunohistochemistry, both agents significantly (p less than 0.001) increased helper-T representation and decreased that by suppressor-T cells. As a result helper/suppressor (H/S) T cell ratios of TIL from untreated tumors (0.73 +/- 0.11) were significantly (p less than 0.001) elevated by both BCG (1.93 +/- 0.39) and CTX (1.40 +/- 0.25). Immunopriming might enhance adoptive immunotherapy by increasing the H/S ratio of TIL prior to their culture.

BCG IN MANAGEMENT OF TRANSITIONAL CELL CARCINOMA INVASIVE TO PROSTATE

Transitional cell carcinoma invading the prostate is a difficult problem to manage. Transurethral resection of the bladder neck followed by intravesical bacillus Calmette-Guerin (BCG) is one suggested option.

Effect of Bcg Upon Functional and Phenotypic Immune Markers in Rats Bearing the Dunning R3327 Mat-Lylu Prostatic Adenocarcinoma

Rats bearing (or not bearing) the Dunning R3327 MAT-LyLu prostatic adenocarcinoma were treated with Bacillus Calmette-Guérin (BCG) and evaluated for immune competence using functional and phenotypic markers. Tumor presence significantly depressed total T and helper T cell representation along with the helper/suppressor T cell ratio. Functional immunity, measured by phytohemmagglutinin (PHA) induced blastogenesis, was also significantly depressed. When BCG was administered to non-tumor bearing animals, it had no effect upon T cell subset distributions but significantly reduced PHA induced blastogenesis. BCG similarly administered to tumor bearing animals did not alter the depressed helper/suppressor T cell ratio found in tumor bearing rats, but did significantly elevate PHA induced blastogenesis. However, these elevated levels of functional immunity in BCG treated tumor-bearing rats remained significantly below normal. These data demonstrate a poor correlation between functional and phenotypic assessments of immune capability.

Adherent Spleen Cell Production of E Series Prostaglandins in Rats Bearing Variants of the R3327 Dunning Prostatic Adenocarcinoma: Effect of Cyclophosphamide

Prostaglandins of the E series (PGE) have been implicated in many facets of immunoregulation, as well as having a possible role in metastatic dissemination. Variant sublines of the Dunning R3327 rat prostatic adenocarcinoma, differing in growth rate, hormonal responsiveness and in propensity for metastasis, were carried in Fisher X Copenhagen F1 animals. Adherent spleen cells were assayed in vitro for their ability to convert arachidonic acid to prostaglandins of the E series. These glass adherent cells presumably include the monocytic and T cell populations which have been implicated as being immunoregulatory. The results indicated that those spleen cells obtained from animals carrying the metastatic R3327-MAT-LyLu subline tumor converted more arachidonic acid to PGEs than cells derived from animals bearing non-metastatic sublines. Cyclophosphamide therapy did not alter such conversion. Multiple regulatory mechanisms for prostaglandin metabolism are suggested.

Altered Helper-T, Suppressor-T Cell Representation in Those with Advanced Stage Prostatic Cancer

Abstract The relative frequencies of mononuclear cell types found in the peripheral blood of patients bearing carcinoma of the prostate were compared by stage and to a control group using monoclonal antibody techniques. Patients with lower stage disease (A,B) had no alteration in subset distribution when compared to a control group, while those with higher stage disease (D) had significant deviations. Stage C patients had lesser increases in suppressor T, monocytic, granulocytic and null cell representation when compared to control and stage D values. Stage D patients had a decreased representation of helper T cells and an increased representation of suppressor T cells with an overall reduction in the total T cell content. In addition, stage D patients had elevated levels of cells, recognized by the polyspecific OKMI antibody, as having antigenicity associated with monocytic, granulocytic and null cell types. Alterations in the ratios between the various T cell populations could provide useful diagnostic/prognostic indicators for patient staging and treatment selection. These findings were extended by comparison of peripheral blood mononuclear cells with primary tumor infiltrates from patients bearing prostatic tumors. Differences in the helper/suppressor-T cell ratios were found, primarily due to reduced helper-T cell presence within the infiltrates.

Isolation and Characterization of Prostatic Tumor Effusions

Abstract In evaluating the relationship between tumor growth and its microenvironment, this preliminary study was undertaken to determine the correlation between prostaglandin (PG) levels, tumor size, histology and their metastatic potential. Peritumoral effusions of the three tumor sublines with different growth rates and metastatic capacity were assayed for levels of prostaglandins E2 and F2α. The sublines of the Dunning prostatic adenocarcinoma tumor model included: R3327 Mat LyLu (fast growing, highly metastatic), R3327G (fast growing, poorly metastatic) and R3327H (slow growing, poorly metastatic). The levels of PGF2α was highly variable with no significant difference between the tumor sublines. However, the mean values of PGF2α in each group were higher when measured in smaller tumors. The levels of PGE2 measured in Mat LyLu tumor effusions were considerably higher than those values obtained from the nonmetastasizing G and H sublines. The data suggests that PGE2 may function as a modulator of tumor cell metastasis.