Pas de Deux: Control of Anti-tumor Immunity by Cancer-Associated Inflammation

Abstract

In many settings, tumor-associated inflammation, supported mainly by innate immune cells, contributes to tumor growth. Initial innate activation triggers secretion of inflammatory, regenerative, and anti-inflammatory cytokines, which in turn shape the adaptive immune response to the tumor. Here, we review the current understanding of the intricate dialog between cancer-associated inflammation and anti-tumor immunity.We discuss the changing nature of these interactions during tumor progression and the impact of the tissue environment on the anti-tumor immune response. In this context, we outline important gaps in current understanding by considering basic research and findings in the clinic. The future of cancer immunotherapy and its utility depend on improved understanding of these interactions and the ability to manipulate them in a predictable and beneficial manner.

Consensus guidelines for the definition, detection and interpretation of immunogenic cell death

“…226 227 These bioactive factors are abundantly produced in response to hypoxia and during chronic inflammation, and are robustly associated with immunoevasion and tumor progression. 228 IL-10 and TGFB1 are secreted by cancer cells and by immunosuppressive immune cells actively recruited to the TME, such as CD4 + CD25 + FOXP3 + regulatory T (T REG ) cells, M2-polarized tumor-associated macrophages (TAMs), and/or myeloid-derived suppressor cells (MDSCs). [229][230][231] Importantly, these immune cell populations express high levels of ectonucleoside triphosphate Open access diphosphohydrolase 1 (ENTPD1, best known as CD39) and 5'-nucleotidase ecto (NT5E, best known as CD73), [232][233][234] two enzymes that cooperate to convert extracellular ATP into adenosine, which also mediates robust immunosuppressive effects.…”

Blocking inflammation to improve immunotherapy of advanced cancer

“…33 Persistent activation of macrophages by neoplastic cells does not favor sustained antitumor T-cell responses. [34][35][36][37][38] This may be exacerbated by IFN-c-associated with Treg reprogramming, which specifically polarizes tumor-associated macrophages into an M1 pro-inflammatory phenotype. 39,40 This is characterized by increased synthesis of IL-6, production of reactive oxygen species (ROS), specific changes of glucose metabolism and a capacity to modulate iron metabolism.…”

Unfolding innate mechanisms in the cancer microenvironment: The emerging role of the mesenchyme

“…Myeloid cells, and especially macrophages and neutrophils, are recruited and infiltrate the tumor site through chemoattractants, mainly cytokines, chemokines, and growth factors that are produced by both cancer cells and the surrounding stroma, including CAFs ( Fig. 1; Shalapour and Karin, 2019). Genetic deletion, cell-specific ablation, or chemical inhibition of their respective receptors, as reported for example for CCR2, CCR5, CXCR2, and CSFR1, results in reduced macrophage and neutrophil/MDSC infiltration and reduced inflammation and tumorigenesis in animal models of cancer (Ijichi et al, 2011;Jamieson et al, 2012;Katoh et al, 2013;Pyonteck et al, 2013).…”

“…Defective activation of DCs results in reduced type I IFN production along with lower costimulatory molecule expression, thus generating a tolerogenic phenotype (Sisirak et al, 2012). Impaired IFN production by DCs, along with IL-10 and TGF-β produced by TAMs and TANs, is also involved in increased T reg cell expansion (Batlle and Massagué, 2019;Shalapour and Karin, 2019;Sisirak et al, 2012). Other important mediators that promote the recruitment or induction of T reg cells are inducible T cell costimulatory ligand (ICOSL) and OX40L produced by DCs (Aspord et al, 2013;Conrad et al, 2012;Faget et al, 2013), CCL22 produced by TAMs, and CCL17 produced by TANs (Maolake et al, 2017;Mishalian et al, 2014).…”