Bystander suppression of tumor growth: Evidence that specific targets and bystanders are damaged by injury to a common microvasculature

The immune response to certain tumors can also suppress the growth of antigenically distinct (bystander) tumor cells injected at the same site. In some cases, bystander suppression occurs during the course of the primary but not the anamnestic response to the same neoplastic cells. We analyzed the pathogenesis of bystander suppression in strain 2 guinea pigs by studying the host response to mixtures of different syngeneic and allogeneic tumors. In nonimmune animals intradermal injection of syngeneic line 1 hepatoma cells was associated with extensive proliferation of fibroblasts and small blood vessels at the tumor periphery, a host response that provided the tumor with a vascularized stroma and invested it in a broad zone of host connective tissue. A leukocytic infiltrate typical of that seen in cellular immune reactions developed by day 7 but was confined predominantly to the connective tissue stroma at the tumor periphery. This distribution permitted few contacts between leukocytes and neoplastic cells but concentrated lymphocytes and other mononuclear luekocytes in the vicinity of the blood vessels supplying the tumor. Tumor rejection appeared to be due to ischemia secondary to extensive microvascular injury, rather than direct contact between individual tumor cells and cytotoxic leukocytes. Syngeneic line 10 hepatoma cells also induced a vascular stroma but elicited less fibroblast proliferation and a more sparse leukocytic infiltrate. The microvasculature of line 10 tumors exhibited minimal endothelial damage and large regions of tumor necrosis did not occur; these neoplasms grew progressively, metastasized, and killed the host. Tumors composed of mixtures of line 1 and line 10 cells evoked a host response identical to that elicited by line 1 tumors. Rejection of these composite tumors also appeared to be a consequence of immunologically nonspecific factors, particularly microvascular damage, which affected both tumor cell lines. The anamnestic response to line 1 cells and the primary of anamnestic responses to allogeneic tumors differed from the primary response to line 1 tumor in two important respects: lymphocytes, basophils, and other inflammatory cells accumulated rapidly (days 1-4) and achieved intimate contact with neoplastic cells; and destruction of specific tumor cells was effected promptly, limiting the development of a significant host connective tissue and vascular response. Under such circumstances, line 10 cells escaped nonspecific destruction and grew progressively.