Figure 1.
Technical characteristics of the main study methods of the tumor microenvironment. FFPE: Formalin-Fixed Paraffin-Embedded and RNA: ribonucleic acid.
Figure 2.
Major cross-talks between the mesenchymal, the immune and the vascular compartments in renal cell carcinoma. Abbreviations: B-reg: B regulatory cells, CD8: cluster of differentiation 8, CXCL2: chemokine (C-X-C motif), EGF: epidermal growth factor, FAP: fibroblast activation protein, FGF: fibroblast growth factor, HIF-1/HIF-2: hypoxia-induced factor-1/hypoxia)-induced factor 2, IDO: indoleamine 2,3-dioxygenase, IFN-γ: interferon γ, IL: interleukin, LAG3: lymphocyte-activation gene 3, MHC: major histocompatibility complex, MDSC: myeloid-derived suppressive cells, NK: natural killer, NO: nitric oxide, PDGF: platelet-derived growth factor, ROS: reactive oxygen species, TGF-β: transforming growth factor beta, TNF-α: tumor necrosis factor alpha, T-reg: T-regulatory cells and VEGF: vascular endothelial growth factor. Legend: The tumor microenvironment is a complex and dynamic network composed both of tumor cells, adaptive and immune cells, endothelial cells and mesenchymal cells as adipocytes and cancer-associated fibroblasts. Structural molecules and extra cellular matrix shape this network. This illustration is not intended to be comprehensive but, rather, to highlight key cross-talks between the immune, the vascular and the mesenchymal compartments. Adipocytes favor tumor progression by inhibiting CD8+ T cells via the leptin release and by stimulating angiogenesis via the release of IL-6, Il-10, TGFB, VEGF or TNF-a. By secreting IDO, IL-6, FAP, TGF-β and IDO, the fibroblasts stimulate MDSC and inhibit CD8 + T cells and NK cells. They also stimulate angiogenesis. The VEGF released by the vascular compartment of renal cell carcinoma has an immunosuppressive effect by inhibiting CD8+ T cells. The interactions between the immune cells are manifold. Basically, FoxP3+ T cells inhibit NK cells, CD8+ T cells and favor macrophage type 2 polarization. B-reg cells stimulate FoxP3+ T cells and inhibit CD8+ T cells. Depending on their polarization, tumor-associated macrophages have pro- or antitumor effects.
Figure 2.
Major cross-talks between the mesenchymal, the immune and the vascular compartments in renal cell carcinoma. Abbreviations: B-reg: B regulatory cells, CD8: cluster of differentiation 8, CXCL2: chemokine (C-X-C motif), EGF: epidermal growth factor, FAP: fibroblast activation protein, FGF: fibroblast growth factor, HIF-1/HIF-2: hypoxia-induced factor-1/hypoxia)-induced factor 2, IDO: indoleamine 2,3-dioxygenase, IFN-γ: interferon γ, IL: interleukin, LAG3: lymphocyte-activation gene 3, MHC: major histocompatibility complex, MDSC: myeloid-derived suppressive cells, NK: natural killer, NO: nitric oxide, PDGF: platelet-derived growth factor, ROS: reactive oxygen species, TGF-β: transforming growth factor beta, TNF-α: tumor necrosis factor alpha, T-reg: T-regulatory cells and VEGF: vascular endothelial growth factor. Legend: The tumor microenvironment is a complex and dynamic network composed both of tumor cells, adaptive and immune cells, endothelial cells and mesenchymal cells as adipocytes and cancer-associated fibroblasts. Structural molecules and extra cellular matrix shape this network. This illustration is not intended to be comprehensive but, rather, to highlight key cross-talks between the immune, the vascular and the mesenchymal compartments. Adipocytes favor tumor progression by inhibiting CD8+ T cells via the leptin release and by stimulating angiogenesis via the release of IL-6, Il-10, TGFB, VEGF or TNF-a. By secreting IDO, IL-6, FAP, TGF-β and IDO, the fibroblasts stimulate MDSC and inhibit CD8 + T cells and NK cells. They also stimulate angiogenesis. The VEGF released by the vascular compartment of renal cell carcinoma has an immunosuppressive effect by inhibiting CD8+ T cells. The interactions between the immune cells are manifold. Basically, FoxP3+ T cells inhibit NK cells, CD8+ T cells and favor macrophage type 2 polarization. B-reg cells stimulate FoxP3+ T cells and inhibit CD8+ T cells. Depending on their polarization, tumor-associated macrophages have pro- or antitumor effects.

Figure 3.
Simplified view of T-cell signatures according to the ccRCC molecular subgroup, adapted from The Human Tumor Microenvironment, Vano et al. Oncoimmunology 2018 [
95]. Legend: ccrcc molecular subgroups have different gene expression immune profiles. Ccrcc 1 are immune-desert, ccrcc 4 are immune-high, ccrcc3 are immune-competent and ccrcc 2 immune-mixed. Light grey means Underexpression; Dark grey means Overexpression.
Table 1.
Prognostic and predictive value of the major TME components in RCC.
TME Element | Status | Associated Prognostic in RCC | Predictive Value for Response to ICI in ccRCC |
---|
Cells | | | |
CD8+ T cells [37,38]. | High density | Poor | Insufficient data |
Regulatory CD4+ T cells [54] | High density | Poor | No |
Tumor-associated Macrophages [50] | High density | Poor | Insufficient data |
B cells [61] | High density | Good | Insufficient data |
Tertiary Lymphoid Structure [56,61] | High density | Good | Insufficient data |
Immune checkpoints | | | |
LAG3 [42,43] | Overexpression | Poor | Insufficient data |
TIM3 [42,43] | Overexpression | Poor * | Insufficient data |
PD-L1 [9,10,91,94,95] | Overexpression | Poor | No ** |
Table 2.
Main technical characteristics and predictive values of the responses of the three major signatures evaluated in metastatic renal cell carcinoma. RT-qPCR: reverse-transcriptase quantitative PCR, IL: interleukin, TGF-β: transforming growth factor β, PFS: progression-free survival and FFPE: Formalin-Fixed Paraffin-Embedded.
Signatures | Study Design | Number of Patients | Genes Involved in the Signature | Treatments | Biological Material Needed | Study Method | Predictive Value of Response |
---|
TKI | ICI |
---|
CIT: classification ccrcc 1-2-3-4 Beuselinck et al. [93] | Retrospective study | 53 (exploratory cohort) 47 (validation cohort) | Inflammation, myeloid activation, myeloid cells migration, Th1/ Th2 polarization, T cell, CMH I, TGFb, IL10, IL17 | Sunitinib | Frozen samples | micro-array (exploratory cohort) RT-qPCR (validation cohort) | YES improved ORR, PFS and OS for ccrcc2 et 3 groups | On going (BIONIKK phase II clinical trial NCT 02960906) |
IMmotion 150 McDermott et al. [62] IMmotion 151 Rini et al. [103] | Randomized phase II and phase III prospective studies | 300 (IMmotion 150) 851 (IMmotion 151) | Angiogenesis, immune response, IFNg, inflammation, myeloid cells | Atezolizumab-bevacizumab vs sunitinib (Atezolizumab-bevacizumab vs atezolizumab pour la phase II) | FFPE samples | RNAseq | YES Improved PFS with sunitinib for Angiohigh | YES Improved PFS with atezolizumab-bevacizumab for Angiolow et Teffhigh |
JAVELIN Renal 101 Choueiri et al. [96] | Randomized phase III prospective study | 886 | Immune response (TcR signalisation, activation-proliferation and T cells differentiation), chimiokines, NK | Avelumab-axitinib vs sunitinib | FFPE samples | RNAseq | NO | YES Improved PFS with avelumab-axitinib for pts with high expression |