Macroimmunology and immunotherapy of cancer

Cytotoxic T lymphocytes (CTLs), associated with Th1 responses, are the most important mediators of resistance against most tumors. We argue that most murine tumors grow progressively when a significant Th2 component to their immune response develops, which is associated with the downregulation of the CTL response. We outline recent evidence that strongly supports this Th2-skewing hypothesis as the prevalent mechanism of tumor escape in murine systems. We describe the conceptual grounds and evidence for the 'threshold hypothesis' that proposes how the Th1/Th2 phenotype of an immune response generated against 'nonliving' antigens is determined. We suggest that this threshold hypothesis also accurately describes how the Th1/Th2 phenotype of murine antitumor immune responses is determined, as this hypothesis can account for the critical and known features of these immune responses. The efficacy of several manipulations that prevent or arrest progressive tumor growth in murine models, through their effects on the antitumor immune response, can be understood within the context of the threshold hypothesis. Indirect evidence supports the view that similar relationships between cancers and the immune system are present in humans. We propose means by which these insights can be employed to optimize the harnessing of protective Th1 CTL immunity against tumors.