Neutralizing tumor-promoting chronic inflammation: a magic bullet?

Abstract

There have been substantial advances in cancer diagnostics and therapies in the past decade. Besides chemotherapeutic agents and radiation therapy, approaches now include targeting cancer cell-intrinsic mediators linked to genetic aberrations in cancer cells, in addition to cancer cell-extrinsic pathways, especially those regulating vascular programming of solid tumors. More recently, immunotherapeutics have entered the clinic largely on the basis of the recognition that several immune cell subsets, when chronically activated, foster tumor development. Here, we discuss clinical and experimental studies delineating protumorigenic roles for immune cell subsets that are players in cancer-associated inflammation. Some of these cells can be targeted to reprogram their function, leading to resolution, or at least neutralization, of cancer-promoting chronic inflammation, thereby facilitating cancer rejection.

Fig. 1

Leukocyte infiltration and complexity in human cancers. (A) CD45⁺ leukocytes (brown staining) in normal human breast tissue compared with invasive ductal carcinoma. These images illustrate the substantial infiltration of leukocytes into neoplastic tissue compared with “normal” tissue counterparts. T indicates tumor nests or tumor cell clusters. (B) Immune cell complexity of adjacent normal tissues (or normal pleura) and the indicated tumors as revealed by polychromatic flow cytometry and expressed as a percentage of CD45⁺ cells. Colors indicate major categories of select immune cell lineages. [Images and data have not been published previously and are courtesy of the Coussens laboratory]

Fig. 2

Induction of T_H2-type immune responses downstream of TSLP. DCs in tumor microenvironments are exposed to cancer-derived factors—for example, TSLP—that skew their maturation toward T_H2-type inflammation, including their expression of OX40L. In this environment, responding T_H2 cells (CD4⁺ T cells) secreting IL-4 and IL-13 promote tumor development either directly or indirectly via macrophages. Direct effects include triggering anti-apoptotic pathways and steroid metabolism in epithelial cancer cells, as well as promoting stromal fibroblast proliferation and differentiation. Indirect effects include triggering secretion of growth (EGF) and pro-angiogenic (VEGF) factors by tumor-infiltrating macrophages that also express inducible nitric oxide synthase (iNOS) and arginase (73) and thereby blunt CD8⁺ T cell proliferation.

Fig. 3

Therapeutic strategies against cancer-induced chronic inflammation. Inhibiting tumor cell–intrinsic proinflammatory functions [such as blunting NF-κB/STAT3/phosphatidylinositol 3-kinase (PI3K)–Akt pathways or downstream effectors]. Moreover, turning lymphocytes into effector T_H1/T_C1 cells necessitates effective reprogramming of type 2 macrophages or immunosuppressive DCs by a concerted action of pattern recognition receptors, the inflammasome platform, or CD40 costimulation, as well as neutralization of immune checkpoint ligand/receptor interaction. In parallel, reducing the accumulation or migration of suppressive myeloid cells in primary sites or distant niches while promoting cytoreduction/debulking with irradiation, cytotoxic compounds, or antiangiogenic molecules may synergistically gear the host/tumor imbalance toward durable tumor regression. HIF-1, hypoxia-inducible factor 1; AMPK, adenosine monophosphate–activated protein kinase; JAK2, Janus kinase 2; CDDO, 2-cyano- 3,12-dioxooleana-1,9(11)-dien-28-oic acid; TLR7, Toll-like receptor 7; COX2, cyclooxygenase; ICD, immunogenic cell death.

Fig. 4

Targeting tumor-promoting chronic inflammation as a therapeutic strategy. (A) Tissue damage results in activation of hard-wired pathways (angiogenic and immune) embedded in all tissues to facilitate healing and homeostasis. (B) Type 1 immune responses, aided by T_H1 cells, eradicate damaged cells to aid the healing prcess. (C) In tissues harboring initiated cells, neoplastic epithelial cells secrete factors such as TSLP, GM-CSF, CSF-1, and TNFα, thereby inducing recruitment of leukocytes that become T_H2-polarized and resulting in chronic activation of angiogenic and tissue remodeling programs, enhanced survival signaling to aid proliferation and blunt cell death, and generation of an immunosuppressive environment that fosters primary tumor development and aids in metastatic disseminations. (D) Effectively counter acting or neutralizing tumor-promoting chronic inflammation may be achieved by resetting or reprogramming the prominent T_H2-based programs activated in cancer; this may result in simultaneously favoring (immunogenic) tumor cell death, where T_H1-based immunity emerges akin to that present during acute inflammation during wound healing, thus enabling a cascade of events favoring cancer rejection, perhaps as monotherapy but more likely in combination with chemotherapy (CTX), radiotherapy (RT), targeted therapy (TT), or antiangiogenic modalities (αANG). DCIS, ductal carcinoma in situ; IDC, invasive ductal carcinoma.