Roles of the Dynamic Tumor Immune Microenvironment in the Individualized Treatment of Advanced Clear Cell Renal Cell Carcinoma

Abstract

Immune checkpoint inhibitors (ICIs) are currently a first-line treatment option for clear cell renal cell carcinoma (ccRCC). However, recent clinical studies have shown that a large number of patients do not respond to ICIs. Moreover, only a few patients achieve a stable and durable response even with combination therapy based on ICIs. Available studies have concluded that the response to immunotherapy and targeted therapy in patients with ccRCC is affected by the tumor immune microenvironment (TIME), which can be manipulated by targeted therapy and tumor genomic characteristics. Therefore, an in-depth understanding of the dynamic nature of the TIME is important for improving the efficacy of immunotherapy or combination therapy in patients with advanced ccRCC. Here, we explore the possible mechanisms by which the TIME affects the efficacy of immunotherapy and targeted therapy, as well as the factors that drive dynamic changes in the TIME in ccRCC, including the immunomodulatory effect of targeted therapy and genomic changes. We also describe the progress on novel therapeutic modalities for advanced ccRCC based on the TIME. Overall, this review provides valuable information on the optimization of combination therapy and development of individualized therapy for advanced ccRCC.

Keywords: clear cell renal cell carcinoma; genomic characteristics; immunotherapy; targeted therapy; tumor immune microenvironment.

Figure 1

Potential mechanisms influencing immunotherapy response in the TIME in ccRCC. (A) The anti-tumor activity of cytokine (IL-2) therapies was primarily mediated by driving the proliferation and activation of NK cells and CD8⁺ TILs. (B) Resistance to cytokine (IL-2) therapies was correlated with the amplification of Tregs level mediated by IL-2 and NK cell dysfunction. IL-6, TGF-β, PGE2, and IDO, as well as lactate and adenosine generated under hypoxic conditions, inhibit the cytotoxic effects of NK cells. (C) The anti-tumor mechanisms of immune checkpoint inhibitors that contribute to the reactivation of CD8⁺ T cells were mediated by blocking the PD-1/PD-L1 and CTLA-4/CD28 pathways. (D) Resistance to immune checkpoint inhibitors is mainly mediated by CD8⁺ TILs anergy, which abundantly express immunosuppressive molecules (e.g., PD-1, CTLA-4, Tim-3, and LAG-3). Tregs and M2-like TAMs secrete IL-10 and TGF-β, which inhibit the cytotoxicity of CD8⁺ TILs and recruit Tregs. Tregs present a stronger immunosuppressive capacity under the action of PD-1 inhibitors. Ligands expressed on M2-like TAMs (including PD-L1/L2, CD80/86, and VISTA) can also promote exhaustion of CD8⁺ TILs. NO, ROS, and Arg-1 produced by MDSCs inhibit the anti-tumor immune function of CD8⁺ TILs, and promote differentiation into M2-like TAMs. Regulatory DCs can also inhibit CD8⁺ T-cell function via the L-arginine metabolic pathway and promote Tregs proliferation.

Figure 2

The Bidirectional Relationship between targeted therapies (VEGF/VEGFR inhibitors) and TIME in ccRCC. (A) Resistance to VEGF/VEGFR inhibitors is due to a complex network of pro-angiogenic factors (IL-1, IL-6, IL-8, MMP-9, VEGF, and FGF2), which promote excessive tumor angiogenesis. IL-1 promotes the production of IL-6, IL-8, and MMP-9, and enhances the expression of VEGF and VEGFR via the Notch pathway. IL-6 upregulates MMP-9 and VEGF levels via the JAK-STAT3 pathway. IL-8 promotes the secretion of VEGF and the self-activation of the VEGFR. MMP-9 enhances the angiogenic effect of VEDF. Tumor produced GM-CSF can also promote MMP-9 and IL-8 production. Finally, HIF-α promotes VEGF secretion. (B) The role of VEGF/VEGFR inhibitors in stimulating the immune response was achieved by blocking the immunosuppressive effect of VEGF. VEGF/VEGFR inhibitors can prevent VEGF-mediated recruitment of TAMs and Tregs, restore DC maturation and antigen presentation, and promote Teff cell migration to tumor microenvironment. (C) Immunosuppression mediated by VEGF/VEGFR inhibitors may have resulted from hypoxia. High doses of VEGF/VEGFR inhibitors can excessively prune tumor vessels, leading to hypoxia in the tumor microenvironment, which facilitates recruitment of Tregs, TAMs and MDSCs.

Figure 3

Genomic characteristics of ccRCC for manipulating the TIME. (A) VHL mutations result in reduced pVHL production and reduced HIF-1α/2α degradation. Excess HIF-1α/2α upregulates the expression of PD-L1 on MDSC, M2-like TAMs, and DCs by binding to the hypoxia response element (HRE). HIF-1α promotes MDSCs to produce iNOS and Arg-1 and to differentiate into M2-like TAMs. HIF-1α promotes the recruitment of Tregs, and mediates the inhibitory effect of M2-like TAMs on the effector function of CD8⁺ TILs. (B) PBRM1 mutation leads to PBAF complex dysfunction, which upregulates interferon-stimulated gene (ISG) expression, thereby enhancing the tumor killing effect mediated by IFN-γ signaling. PBAF inactivation also promotes the secretion of CXCL9 and CXCL10 by tumor cells. BAP1 mutations are associated with the immuno-exhausted tumor microenvironment. SETD2 mutations are associated with the immune-silenced tumor microenvironment. (C) PTEN mutations activate the P13K-Akt pathway, resulting in upregulation of VEGF, CCL2, and IL-23 expression, which contribute to the recruitment of Tregs, DCs, and MDSCs. (D) Frameshift INDELs and HERV expression can generate abundant neoantigens, which stimulate the production of neoantigen-specific T cells. Arm level SCNA can disrupt the antigen-presenting capacity of MHC on tumor cells, resulting in inactivation of tumor-specific immune responses.