Regulation of T- and B lymphocyte responses to mitogens by tumor-associated macrophages: the dependency on the stage of tumor growth.
This preliminary investigation was concerned with the hypothesis that macrophages associated with tumors induced to regress temporarily by the action of cyclophosphamide (CY) have the capacity to suppress local T- or B lymphocyte responses which otherwise might cause permanent regression. Cultures of adherent cells, predominantly tumor-associated macrophages ( TAMs ), isolated from two C57BL/6J (B6) sarcomas, MCA/76-9 and 76-64, after various periods of tumor growth or after CY injection (240 mg/kg) were shown to suppress or enhance the response of 10(6) B6 normal spleen cells to stimulation by concanavalin-A (Con A) or lipopolysaccharide (LPS). At any given time point, the extent of suppression or enhancement induced by adherent cells isolated from tumors after CY injection was similar to that induced by cells from progressing tumors and appeared to be more dependent on the time after the initial injection of tumor cells than on drug treatment per se. Thus, adherent cells suppressed Con A and LPS responses when they were isolated either from small (0.5 g) or large (greater than 1.5 g) progressing tumors or from tumors 4-9 days after CY injection. However, during the logarithmic phase of tumor growth or within 4 days of injecting CY, adherent cells enhanced spleen cell mitogenic responses, particularly to LPS stimulation. The cultures of putative TAMs isolated at the various time points were seen to contain varying proportions of polymorphonuclear cells (PMNs), the proportions coinciding with the period of reduced spleen cell mitogenic responses. Cultures prepared from small or large progressing tumors contained about 10% or 20-30% PMNs, respectively, while those from tumors tested during the log phase contained less than 5% PMNs. Cultures from tumors removed within 4 days of injecting CY contained less than 5% PMNs while those prepared from tumors tested at later times contained as high as 25% PMNs by 9 days after CY injection. A comparison of peritoneal PMNs and macrophages from non-tumor-bearing mice in terms of their ability to influence mitogenesis indicated that PMNs at high ratios (1 PMN:2 spleen cells) could suppress responses directly. Lower ratios had either small suppressive effects or no effects but in no case was enhancement of responses seen. Peritoneal macrophages suppressed responses at a ratio of 1 macrophage:10 spleen cells but enhanced responses at ratios of 1 macrophage:100 or 1,000 spleen cells. The overall data indicated that the microenvironment of the tumor site may modulate the functional activity of macrophages, or their subpopulations, during their potential regulation of T- and B-cell responses.(ABSTRACT TRUNCATED AT 400 WORDS)
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D003208:Concanavalin A / Q000494:pharmacology; D003520:Cyclophosphamide / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008934:Mitogens / Q000494:pharmacology*; D009374:Neoplasms, Experimental / Q000276:immunology*; D012208:Rhabdomyosarcoma / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D008934:Mitogens; D003208:Concanavalin A; D003520:Cyclophosphamide