Immunotherapy in preneoplastic disease: targeting early procarcinogenic inflammatory changes that lead to immune suppression and tumor tolerance

Abstract

Recent advances in immunotherapy have demonstrated that single agent vaccines can be effective when given as primary prevention before exposure to the causative agent, and partially effective in some patients with existing cancer. However, as tumors develop and progress, tumor-induced immune suppression and tolerance present the greatest barrier to therapeutic success. Preneoplastic disease represents an important opportunity to intervene with tumor antigen-targeted vaccines before these mechanisms of immune evasion outpace efforts by the immune system to destroy precancerous cells. However, as we discuss in this review, emerging evidence suggests that procarcinogenic inflammatory changes occur early in cancer development, in both patients and mouse models of cancer progression. Defining early inhibitory signals within tumor microenvironments will yield insights that can eventually be used in the clinic to target these events and deliver treatments that can be used in addition to cancer vaccines to prevent premalignant and early invasive cancers.

Figure 1

Inflammatory progression model for pancreatic ductal adenocarcinoma (PDA). Previous models have described the timing of genetic alterations in relation to different PanIN stages, which represent increasing degrees of cellular atypia, loss of normal tissue structure, and genetic abnormality. We propose a new model incorporating the relationship between genetic mutations and gene expression changes with inflammatory cytokines and signaling present in the tumor microenvironment, as well as with cell populations recruited to the tumor microenvironment. Using PDA as an example, we show that genetic mutations, such as Kras, can induce secretion of inflammatory cytokines, such as GM-CSF and IL-8, which induce and recruit immature myeloid and granulocytic cells, as well as suppressive T_reg cells, that then drive immune tolerance and escape. These procarcinogenic immune cells can contribute to an inflammatory milieu, that is capable of suppressing effector T cell responses, recruiting additional suppressive cells, modifying tumor vasculature, and contributing to further DNA damage and mutations, all of which results in cancer progression.