Immunotherapy in Renal Cell Carcinoma: The Future Is Now

Abstract

Renal cell carcinoma is the third type of urologic cancer and has a poor prognosis with 30% of metastatic patients at diagnosis. The antiangiogenics and targeted immunotherapies led to treatment remodeling emphasizing the role of the tumour microenvironment. However, long-term responses are rare with a high rate of resistance. New strategies are emerging to improve the efficacy and the emerging drugs are under evaluation in ongoing trials. With the different treatment options, there is an urgent need to identify biomarkers in order to predict the efficacy of drugs and to better stratify patients. Owing to the limitations of programmed death-ligand 1 (PD-L1), the most studied immunohistochemistry biomarkers, and of the tumor mutational burden, the identification of more reliable markers is an unmet need. New technologies could help in this purpose.

Keywords: PD-1; PD-L1; biomarkers; emerging drugs; immune checkpoint inhibitors; immunotherapy; ongoing trials; renal cell carcinoma.

Figure 1

European Association of Urology Guidelines on Renal Cell Carcinoma. IMDC = International Metastatic Renal Cell CarcinomaDatabase Consortium; OS = overall survival; Oxford level of evidence: [1b] = based on one randomised controlled phase 3 trial; [2a] = based on one randomised controlled phase 2 trial; [2b] = subgroup analysis of a randomised controlled phase 3 trial; [4] = expert opinion. a = No OS benefit proven.

Figure 2

T-cell activation or inhibition is the result of an integrated and sequential intracellular signal cascade after MHC-peptide recognition by TCR. Abbreviations: GITR = Glucocorticoid-Induced TNF Receptor, ICOS = Inducible co-stimulator, OX40 = CD134, TCR = T-Cell Receptor, PD1 = Programmed Death 1, CTLA4 = Cytotoxic T-lymphocyte Antigen-4, LAG3 = Lymphocyte-associated gene 3, TIM3 = Tcell Immunoglobulin and Mucin domain-3, TIGIT = T-cell Immunoglobulin and ITIM domain, VISTA = Vdomain Immunoglobulin Suppressor of T-cell Activation.

Figure 3

Tumor microenvironment is commonly defined as the co-existence of tumor cells interacting with resident and infiltrating host cells, secreted factors and extracellular matrix proteins. Among them, immunosuppressive cells are recruited in the tumor microenvironment by chemotaxis and are responsible for immunomodulatory cytokines production enhancement and decreased essential amino acids availability, resulting in favorable conditions for tumor growth. MDSC = Myeloïd-derived suppressive cells; T-cell = T lymphocyte; T-reg = Regulator lymphocyte; M2 = Type 2 macrophage; DC = dendritic cell; TGBß = tumor growth factor ß; A2aR = adenosine 2a receptor; ATP = adenosine triphosphate; AMP = adenosine monophosphate; IL10 = interleukin-10; MHC = major histocompatibility complex; PD1 = programmed death protein 1; PDL1 = programmed death ligand 1; IDO1 = indoleamine 2,3 dioxygenase 1; CTLA4 = cytotoxic T-lymphocyte antigen-4; CCL22 = C-C motif chemokine Ligand L22; CCR4 = C-C motif chemokine receptor 4; M1 = type 1 macrophage; INFγ = interferon γ; TNF α = tumor necrosis factor α.