Macrophages, innate immunity and cancer: balance, tolerance, and diversity

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Smouldering inflammation is a component of the tumor microenvironment and represents the 7th hallmark of cancer. Tumor-associated macrophages (TAM) have served as a paradigm for cancer promoting inflammation. Tumor-associated macrophages orchestrate various aspects of cancer, including: diversion and skewing of adaptive responses; cell growth; angiogenesis; matrix deposition and remodelling; the construction of a metastatic niche and actual metastasis; response to hormones and chemotherapeutic agents.

T and B cells or cancer cell-derived signals orchestrate the functional reprogramming of TAM. In general TAM acquire M2-like properties and resemble ‘tolerant’ macrophages, though there is diversity in pathways and phenotypes in different tumors. TAM can also express antitumor activity. Thus, in response to microenvironmental signals, TAM can exert dual influence on tumor growth and progression.

Introduction

After a long eclipse, in recent years different lines of work have lead to a renaissance of the inflammation–cancer connection [1, 2, 3]. Selected forms of chronic inflammation predispose to cancer, including microbial infections (e.g. Helicobacter pilori for gastric cancer and mucosal lymphoma), autoimmune diseases (e.g. colitis-associated cancer), and inflammatory conditions of uncertain origin (e.g. prostate cancer). Usage of non-steroidal anti-inflammatory agents protects against various tumors. Moreover, smouldering inflammation is a key characteristic of the microenvironment of most neoplastic tissues, including those not etiologically related to inflammatory processes. Inflammation has been suggested to represent the 7th hallmark of cancer [4].

Recent efforts have shed new light on molecular and cellular pathways linking inflammation and cancer [2]. Two pathways link inflammation and cancer. In the intrinsic pathway, activation of different classes of oncogenes drives the expression of inflammation-related programs that guide the construction of an inflammatory microenvironment. In the extrinsic pathway, inflammatory conditions promote cancer development (e.g. colitis-associated cancer of the intestine). Key orchestrators at the intersection of the intrinsic and extrinsic pathway include transcription factors (e.g. NF-κB; Stat3; HIF) [5, 6•, 7], cytokines (e.g. TNF), and chemokines. Thus, inflammation is a key component of the tumor microenvironment and a target for pharmacologic intervention.

Tumor-associated macrophages (TAM) are a major component of leukocytic infiltrate of tumors and have served as a paradigm for cancer-related inflammation [2, 8, 9]. Macrophages are a double-edged sword, with the potential to express pro and anti-tumor activity (the macrophage balance [10, 11]), the former prevailing in established neoplasia. Here we will focus on selected molecular pathways underlying TAM recruitment and polarization, emphasizing the dual potential of cancer-related inflammation [12] and the diversity of pathways and functions in different tumors.

Section snippets

Chemokines in TAM recruitment and carcinogenesis: doubt no more

TAM recruitment in tumors is mediated by cytokines belonging to different classes including colony stimulating factor-1 [13], vascular endothelial growth factor and chemokines [14]. Moreover, the C5a complement component that interacts with a G protein coupled receptor as chemokines do, has also been recently shown to play a role in leukocyte recruitment in cancer-related inflammation (CRI) [15]. Thus, members of different molecular families can contribute to the shaping of CRI.

Inflammatory

Orchestration of TAM function and polarization: extracellular signals

Plasticity is a hallmark of mononuclear phagocytes. In response to diverse signals, macrophages undergo polarized activation. Classically activated (M1) macrophages, following exposure to interferon γ (IFNγ), have tumoricidal activity and elicit tissue destructive reactions. In response to IL-4 or IL-13, macrophages undergo alternative (M2) activation [10, 27]. In general, M2 cells obtained in response to IL-4 are oriented to tissue repair and remodelling, immunoregulation, and tumor promotion [

Molecular determinants of TAM functions

As mentioned above, TAM generally have phenotype and functions similar to alternative or M2 macrophages [2, 22•]. For example, TAM express low levels of the major histocompatibility complex class II and reduced antimicrobial and tumoricidal activity, while increasing production of mediators that promote angiogenesis, such as vascular endothelial growth factor and cyclo-oxygenase-2 (COX-2)-derived prostaglandin E2, as well as the anti-inflammatory cytokine IL-10 [2]. Another hallmark feature of

Promotion of invasion and metastasis

Macrophages and some of their products (IL-1; TNF; IL-6) have long been known to increase metastasis [2] and recent work has provided new evidence [33••, 34, 55, 56, 57]. In particular, cells of hematopoietic origin and specifically myelomonocytic cells have been shown to home and condition the premetastatic niche. Here they form a secondary niche that favors secondary localization of cancer [36, 58, 59•].

Tipping the balance

Certain forms of inflammation are protective in a preventive or therapeutic setting [2, 60, 61]. An immune response has long been known to contribute to the outcome of chemotherapy. It has now been shown that dying tumor cells can be cross presented by dendritic cells and trigger a protective immune response via a TLR4-MyD88 pathway [62]. Inflammasome activation and IL-1β production underlie ultimate activation of protective immunity [63••]. Association of TLR4 and PrX7 polymorphisms with

Concluding remarks: balance, tolerance, and diversity

Recent results have highlighted a striking similarity in terms of transcriptional profile, functional properties, and underlying transcription factors between TAM and ‘tolerant’ macrophage [51]. Tolerant macrophages belong to the wide spectrum and universe of M2-like polarized phagocytes. The finding that PMN have unsuspected plasticity and are subject to a P1–P2 balance in the tumor microenvironment [28] calls for a reappraisal of their role and significance in cancer-related inflammation.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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