Impact of inflammation and immunotherapy in renal cell carcinoma

Abstract

Substantial research attention has been directed at exploring the mechanisms and treatment of renal cell carcinoma (RCC). Indeed, the association between inflammation and tumor phenotypes has been at the center of cancer research. Concomitant with research on the inflammation response and inflammatory molecules involved in RCC, new breakthroughs have emerged. A large body of knowledge now shows that treatments targeting inflammation and immunity in RCC provide substantial clinical benefits. Adequate analysis and a better understanding of the mechanisms of inflammatory factors in the occurrence and progression of RCC are highly desirable. Currently, numerous RCC treatments targeted at inflammation and immunotherapy are available. The current review describes in detail the link between inflammation and RCC.

Keywords: immunotherapy; inflammation-related pathway; inflammatory factor; renal cell carcinoma; tumor microenvironment.

Figure 1.

mTOR pathway affects tumor cell growth and proliferation. mTOR consists of two intracellular complexes, mTORC1 and mTORC2. Growth factors and amino acids activate mTORC1, thereby activating lipid kinase PI3K. Phosphorylation of PIP2 by PI3K then produces PIP3, which phosphorylates and activates AKT via the intermediate kinase PDK1. PTEN is a phosphatase that negatively regulates PI3K to dephosphorylate PIP3 back to PIP2. Once this pathway is activated, AKT phosphorylates and inhibits the TSC phosphorylation (AKT can also be activated by mTORC2). TSC is able to negatively regulate mTORC1 by inhibiting Rheb, a GTP-binding protein. AKT can disable this inhibition and activate the mTOR pathway. AMPK reduces cellular ATP storage and increases the AMP:ATP ratio, inhibiting mTOR by the phosphorylation and activation of TSC2. After AKT is activated, mTORC1 phosphorylates p70S6K and 4EBP to promote protein translation and enhance cell growth. mTOR, mechanistic target of rapamycin; mTORC, mTOR complex; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-triphosphate; TSC, tuberous sclerosis complex; Rheb, Ras homolog enriched in brain; PDK1, 3-phosphoinositol-dependent kinase-1; p70S6K, 70 kDa ribosomal protein S6 kinase; 4EBP, eukaryotic translation initiation factor 4E-binding protein 21.

Figure 2.

Inflammatory molecules associated with RCC. The role of different inflammatory factors and immune cells in RCC-promoting inflammation and RCC tumor immunity. RCC, renal cell carcinoma; IL, interleukin; STAT, signal transducer and activator of transcription; TNF, tumor necrosis factor; NF-κΒ, nuclear factor-κB; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; CSF-1, colony-stimulating factor 1; CSF-1R, CSF-1 receptor; CXCL, chemokine (C-X-C motif) ligand; CXCR, CXC chemokine receptor; MMP, matrix metalloproteinase; TAM, tumor-associated macrophage; MDSC, myeloid-derived suppressor cell.

Figure 3.

IL-6 pathway promotes RCC development. IL-6 (pink stars) binds first to the membrane-bound non-signaling IL-6R (green diamonds). Non-signaling IL-6R is activated as IL-6R (green square), which can be signal transduced. After recruitment of 2 gp130 (brown-colored rectangular squares) molecules, the signaling complex is formed and signal transduction is induced (brown-colored squares represent ‘dimerization of gp130’). Signaling via membrane-bound IL-6R can promote the development of RCC by activating STAT3, a potential regulator of HIF-1-mediated VEGF expression transcription. This may be associated with the proliferation of RCC. Human NEU3 plays an important role in cell differentiation and transmembrane signal transduction, and its expression is associated with IL-6. NEU3 is sensitive to IL-6 signaling via the PI3K pathway. Overexpression of NEU3 can enhance the action of IL-6, inhibit apoptosis and promote cell migration. IL-6, interleukin-6; IL-6R, IL-6 receptor; RCC, renal cell carcinoma; gp130, glycoprotein 130; STAT3, signal transducer and activator of transcription 3; HIF-1, hypoxia-inducible factor 1; VEGF, vascular endothelial growth factor; NEU3, plasma membrane-associated sialidase; PI3K, phosphatidylinositol 3-kinase; EMT, epithelial-mesenchymal transition.