The tumor microenvironment and its role in promoting tumor growth

Abstract

The tumor microenvironment is created by the tumor and dominated by tumor-induced interactions. Although various immune effector cells are recruited to the tumor site, their anti-tumor functions are downregulated, largely in response to tumor-derived signals. Infiltrates of inflammatory cells present in human tumors are chronic in nature and are enriched in regulatory T cells (T(reg)) as well as myeloid suppressor cells (MSC). Immune cells in the tumor microenvironment not only fail to exercise antitumor effector functions, but they are co-opted to promote tumor growth. Sustained activation of the NF-kappaB pathway in the tumor milieu represents one mechanism that appears to favor tumor survival and drive abortive activation of immune cells. The result is tumor escape from the host immune system. Tumor escape is accomplished through the activation of one or several molecular mechanisms that lead to inhibition of immune cell functions or to apoptosis of anti-tumor effector cells. The ability to block tumor escape depends on a better understanding of cellular and molecular pathways operating in the tumor microenvironment. Novel therapeutic strategies that emerge are designed to change the pro-tumor microenvironment to one favoring acute responses and potent anti-tumor activity.

Figure 1

A diagram depicting the tumor microenvironment. Interactions of various cells with each other, fibroblasts (F) in the tumor stroma and blood vessels (V) are indicated by arrows. Although the tumor (TU) generates signals inducing dysfunction and death of immune cells, the latter are a source of signals promoting tumor growth. TAM, tumor-associated macrophages; DC, dendritic cells; EL, effector lymphocytes; T_reg, regulatory T cells; TA, tumor-derived antigens; ROS, reactive oxygen species; PGE₂, prostaglandin E₂.

Figure 2

Accumulation and expansion of T_reg in the tumor microenvironment may be a result of the cross talk between the tumor and DC. The tumor coopts DC differentiation, and in the presence of tumor-derived factors, immature DC develop abnormalities in APM, have decreased expression levels of MHC molecules, upregulate B7–H1 (PD-L1) and produce excess of IL-10 and TGF-β1. Cross-presentation of TA by these DC to T cells (as in the lower part of figure) lead to emergence of T_reg and their expansion. Once generated, T_reg interfere with functions of anti-tumor effector cells (CTL). Even if cross-presentation of TA by DC to naive CD8 + T cells is successful (as in the upper part of figure), T_reg proceed to block CTL functions. Reproduced with changes from Ferrone and Whiteside, 2007.

Figure 3

Tumors recruit MSC from the bone marrow by means of tumor-derived soluble factors. Immature myeloid cells migrate to lymph nodes, where DC cross-prime T cells, and interfere with this process. They also migrate to the tumor site and become tumor-associated MSC, which are adept in blocking T cell functions through the production of arginase I and activation of iNOs.

Figure 4

Mechanisms responsible for `immunoediting' of tumor cells in the tumor microenvironment. The various mechanisms listed collaborate in immunoediting of the tumor cells. The tumor, stromal cells and infiltrating leukocytes all contribute to pro-inflammatory milieu. Infiltrating immune cells and stromal elements are re-programmed by the tumor to the pro-inflammatory mode favoring its survival. In this milieu, the tumor evolves a phenotype allowing it to escape and to counterattack immune cells. Tumor stem cells are resistant to anti-tumor therapies and thus represent yet another means of escape.