Immunotherapy of Clear-Cell Renal-Cell Carcinoma

Abstract

Clear-cell Renal-Cell Carcinoma (ccRCC) is the most common type of renal-cell carcinoma (RCC). In many cases, RCC patients manifest the first symptoms during the advanced stage of the disease. For this reason, immunotherapy appears to be one of the dominant treatments to achieve a resolution. In this review, we focus on the presentation of the main immune checkpoint proteins that act as negative regulators of immune responses, such as PD-1, CTLA-4, LAG-3, TIGIT, and TIM-3, and their respective inhibitors. Interleukin-2, another potential component of the treatment of ccRCC patients, has also been covered. The synergy between several immunotherapies is one of the main aspects that unites the conclusions of research in recent years. To date, the combination of several immunotherapies enhances the efficacy of a monotherapy, which often manifests important limitations. Immunotherapy aimed at restoring the anti-cancer immune response in ccRCC, involved in the recognition and elimination of cancer cells, may also be a valid solution for many other types of immunogenic tumors that are diagnosed in the final stages.

Keywords: clear-cell renal-cell carcinoma; immune checkpoint proteins; immunotherapy combinations; interleukin 2.

Figure 1

Intracellular signaling triggered by the interaction of PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT with their respective ligands: the binding between PD-1 and PD-L1/PD-L2 induces phosphorylation of ITIM and ITSM, constituting the cytoplasmic domain of PD-1. SHP-1 and SHP-2 are subsequently recruited, leading to the inhibition of the PI3K-Akt and PLCy1-Ras/MEK/ERK pathways. CD80/CD86 interacting with CTLA-4 triggers the phosphorylation of the intracellular YVKM domain and the consequent recruitment of SHP-2 and activation of PP2A, which hamper the PI3K-Akt pathway. The exact mechanism triggered by the cytoplasmic tail of LAG-3, consisting of the FxxL, KIEELE, and EP domains, upon interaction with its ligand MHC-II, has not yet been clearly defined. Binding of TIM-3 to Gal-9 induces the phosphorylation of Tyr256 and Tyr263 in its intracellular tail resulting in the displacement of Bat-3 and consequently on the dephosphorylation of Lck, which leads to the downregulation of ZAP70/LAT/PLCγ1/Ca²⁺ pathway. Following the binding of TIGIT to CD155, the ITIM and ITT domains of the intracellular tail are phosphorylated. The complex binds then to Grb2 and recruits SHIP-1 which promotes the inhibition of PI3K-Akt and MAPK pathways. Overall, these signalings prevent the optimal activation and function of the immune cells involved in hindering tumor development (Arrows in the image indicate active pathways. Arrows underneath the curly brackets indicate “decrease”. “???” indicate that the pathway implicated is unknown). Created with BioRender.com.

Figure 2

Immune checkpoint receptors associated with their respective ligands and inhibitors: immune checkpoints such as PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT, expressed on T and NK cells, bind their respective ligands on RCC cells, triggering a negative signal to the immune cell response. Created with BioRender.com.

Figure 3

IL-2 therapy mechanism: IL-2 influences tumor growth directly and indirectly. The indirect action is induced by the IL-2 stimulation of PMBCs, especially T and NK cells, for a few days. This gives rise to LAK cells that show cytotoxic abilities against tumor cells, including renal carcinoma cells, via the release of perforin, granzyme A (GrA), granzyme B (GrB), TNFα, and IFNγ. The direct action of IL-2 is driven by the presence of an IL-2 receptor expressed on the tumor cells. Created with BioRender.com.