Differential Induction of Hematopoiesis and Immune Suppressor Cells in the Bone Marrow Versus in the Spleen by Lewis Lung Carcinoma Variants

Abstract

Mice bearing large (greater than or equal to 3 g) metastatic and nonmetastatic Lewis lung carcinoma (LLC) tumors were studied to determine if the tumor variants differentially induced bone marrow versus splenic hematopoiesis and the appearance of hematopoiesis-associated immune suppressor cells. The metastatic LLC-C3 and nonmetastatic LLC-C8 tumors were equal in their stimulatory effects in vivo on both the number of bone marrow myeloid progenitor cells (CFU) and the appearance of bone marrow immune suppressor cells. In contrast, the tumor variants differed in their effects on the spleen, with the metastatic tumors causing a more pronounced increase in the number of nucleated cells and CFU, a reduced blastogenic responsiveness to concanavalin (Con-A), and an increased suppressor cell activity than nonmetastatic LLC-C8 tumors. The splenic suppressor cells of mice bearing large LLC-C3 tumors resembled the bone marrow suppressor cells which we previously described (Young et al.: Cancer Res. 47, 100, 1987) in that they were nonadherent to nylon wool, sensitive to treatment with L-leucine methyl ester, insensitive to treatment with complement and Thy-1.2, MG-1.2, asialo-GM1, or anti-IgM antibodies, and mediated their suppression through a mechanism which was only partially indomethacin sensitive. The stimulatory effects on hematopoiesis and suppressor cells by the LLC variant tumors may have been mediated by the tumor-derived colony stimulating factor (CSF) activities. Bone marrow cell proliferation and colony formation were stimulated in vitro by culture supernatants of metastatic LLC-C3 cells and, to a lesser degree, of nonmetastatic LLC-C8 cells. These colony-stimulating factor (CSF)-containing supernatants also induced normal bone marrow cells to become immune suppressive. In contrast, supernatants of only LLC-C3 cells, and not of LLC-C8 cells, stimulated in vitro growth of splenic CFU from LLC-C3-bearing mice; spleen cells from normal mice and from LLC-C8 bearers were unresponsive to supernatants of the LLC variants. These results suggest that CSF produced by either the metastatic LLC-C3 or the nonmetastatic LLC-C8 tumors could concurrently stimulate bone marrow hematopoiesis and the appearance of bone marrow suppressor cells. However, the metastatic LLC-C3 tumor cells, and not the nonmetastatic LLC-C8 cells, could also cause expansion of progenitor cells and hematopoiesis to the spleen and, consequently, induce the appearance in the spleen of hematopoiesis-associated immune suppressor cells.

Opposing effects of fibrosarcoma cell‐derived IL‐1α and IL‐1β on immune response induction

“…Tumor-derived IL-1b accounts for strong immunosuppression IL-1b supports MDSC expansion by initiating an inflammatory response, [21][22][23][24][25] which is in line with the abundance of Gr-1 1 and CD11b 1 cells in IL-1a 2/2 tumors (Fig. 3a).…”

“…MDSC, which frequently expand during tumor growth, 22,23 were most abundant in IL-1b-competent tumor-bearing mice, which is in line with IL-1b contributing to MDSC expansion. 21,24,25 Importantly, an in vivo reduction of MDSC by ATRA treatment 42 resulted in retarded growth of an IL1a 2/2 , IL-1b-competent tumor line and partly suppressed in vivo growth of an IL-1-competent tumor line. Thus, tumor-derived IL1b strongly fosters MDSC expansion and activation.…”

“…16,21,24,25 There is abundant evidence that in chronic diseases like cancer T-cell activation is controlled by an array of immunoregulatory mechanisms. 26 Attention has recently focused on 2 subsets of hematopoietic cells involved in these immunoregulatory processes, CD4…”

Tracking of intertissue migration reveals the origins of tumor-infiltrating monocytes

“…However, in certain disease states, organs such as the liver and spleen become sites of extramedullary hematopoiesis (8,9). In tumor-bearing mice myeloid cells accumulate in the spleen (10)(11)(12), making this organ a candidate source of tumor-infiltrating cells. Recent reports propose that a rapidly mobilized reservoir of monocytes in the spleen contributes significant numbers of infiltrating cells in acute and chronic inflammatory conditions including myocardial infarction (13)(14)(15), stroke (14), atherosclerosis (15), and cancer (16,17).…”

Combined GM-CSF treatment and M-CSF inhibition of tumor-associated macrophages induces dendritic cell-like signaling in vitro

“…Among these cells, CD11b + Gr -1 + granulocyte-lineage cells, also referred to as myeloid-derived suppressor cells (4,5), are present in bone marrow, spleen, and tumor tissue of the tumor-bearing host and suppress T-cell functions (6)(7)(8)(9). In contrast, tumor-infiltrating monocyte/macrophage-lineage cells, referred to as tumor-associated macrophages (TAM), show immunosuppressive properties (10).…”