Histological analysis of IL-2 induced regression of murine solid SL2-tumors

Abstract

When DBA/2 mice are inoculated both intraperitoneally (i.p.) and subcutaneously (s.c.) with syngeneic SL2 lymphoma cells and treated i.p. on day 10-14 with 20,000 units IL-2/day, about 50% of the mice reject both the ascitic tumour and the s.c. tumour. During IL-2 therapy large areas of necrosis appear in the solid SL2 tumours between day 12 and 15. Immunohistochemical studies show that only a small number of infiltrating cells is present in the tumours. The percentage of macrophages (MHC-II+) in the tumours is about 1 and the percentage of T-lymphocytes (alpha beta-TCR+) about 0.5. No differences in the numbers of infiltrating cells are seen in untreated and IL-2 treated tumour bearing mice. The tumour surrounding infiltrate consists mainly of mononuclear cells: about 50% macrophages, 20% CD8+ cells, and 15% CD4+ cells. No tumour-infiltrating cells were found that express the IL-2 receptor. We conclude that direct cytotoxic activity of tumour infiltrating cells cannot account for the rapid occurrence of necrosis. When L3T4+ cells were eliminated by treating the mice with alpha-L3T4 monoclonal antibodies before tumor inoculation and treatment with rIL-2, tumor eradication did not occur. So, L3T4+ helper T-cells are essential for IL-2-mediated tumour regression. Exogenous rIL-2 is not directly responsible for the induced tumour regression. A significant stagnation of intratumoural bloodflow is observed after histological analysis; yet it still needs to be determined whether this is the primary cause or consequence of the observed necrosis.

IL-2 Intratumoral Immunotherapy Enhances CD8+ T Cells That Mediate Destruction of Tumor Cells and Tumor-Associated Vasculature: A Novel Mechanism for IL-2

“…IL-2 has been shown to inhibit (12,13) or induce (14,15) vascularity in different systems. IL-2 has also been reported to cause necrosis or induce an antitumor response that may involve lymphocytes (16,17), neutrophils, macrophages (18,19), NK cells (20,21), and/or T cells (22,23).…”

“…We observed increased necrosis in some of our IL-2-treated mice (data not shown). A few studies have shown that IL-2 can affect blood vessels by increasing (14,15) or decreasing vasculature (12,13). Similarly, IL-2 has been shown to trigger the vascular leakage system, which results in endothelial cell damage (45).…”

“…Importantly, this study demonstrates a novel mechanism for IL-2 in antitumor immunity via immune-related destruction of tumor-associated vasculature. IL-2 can affect many different cell types resulting in antitumor immunity, including nonspecific cells, such as NK cells (12,50,51), neutrophils, or macrophages (18,19). IL-2 therapy failed to work in nude mice that lack T cells but still have functional NK cells, suggesting that NK cells on their own are not sufficient for IL-2 induced regression.…”

Endogenous natural killer cells do not play a role in antitumor effects induced by interleukin-2 in a syngeneic rat colon tumor model

“…For example, IL-2 treatment might disturb the tumor vascular supply. In this context Maas et al [18] showed, in a syngeneic mouse model, that IL-2-mediated tumor regression was dependent on T helper cells but also associated with stagnation of intratumoral blood¯ow. Furthermore, they showed that intratumorally injected IL-2 did not result in an increased tumor in®ltration by immune cells: only very few immune cells were found to be in contact with tumor cells both in IL-2-treated animals and in control animals.…”