The Interplay between Inflammation, Anti-Angiogenic Agents, and Immune Checkpoint Inhibitors: Perspectives for Renal Cell Cancer Treatment

Abstract

Treatment options for metastatic renal cell carcinoma (RCC) have been expanding in the last years, from the consolidation of several anti-angiogenic agents to the approval of immune checkpoint inhibitors (ICIs). The rationale for the use of immunomodulating agents derived from the observation that RCC usually shows a diffuse immune-cell infiltrate. ICIs target Cytotoxic T Lymphocytes Antigen 4 (CTLA-4), programmed death 1 (PD-1), or its ligand (PD-L1), showing promising therapeutic efficacy in RCC. PD-L1 expression is associated with poor prognosis; however, its predictive role remains debated. In fact, ICIs may be a valid option even for PD-L1 negative patients. The establishment of valid predictors of treatment response to available therapeutic options is advocated to identify those patients who could benefit from these agents. Both local and systemic inflammation contribute to tumorigenesis and development of cancer. The interplay of tumor-immune status and of cancer-related systemic inflammation is pivotal for ICI-treatment outcome, but there is an unmet need for a more precise characterization. To date, little is known on the role of inflammation markers on PD-1 blockade in RCC. In this paper, we review the current knowledge on the interplay between inflammation markers, PD-1 axis, and anti-angiogenic agents in RCC, focusing on biological rationale, implications for treatment, and possible future perspectives.

Integrative clinical and molecular analysis of advanced biliary tract cancers on immune checkpoint blockade reveals potential markers of response

“…Indeed, several inflammatory markers have been described as prognostic factors in cancer patients. 33 Herein, we also assessed a wide array of systemic inflammatory markers, including LDH, CRP, SII, GPS, PI, PNI, as well as several tumor markers, including CEA, CA125, and CA199. However, none of them showed a clear association with immunotherapy outcome.…”

Lactotransferrin Downregulation Drives the Metastatic Progression in Clear Cell Renal Cell Carcinoma

“…In addition to EMT, a recent review article demonstrated that the systemic inflammation may damage the immune system, thereby allowing tumoral invasion [11]. These findings highlighted that LTF may inhibit the metastatic potential of ccRCC cells through the suppression of inflammation [17] and the enhancement of cancer immune surveillance [11]. However, further studies are necessary to evaluate the possible mechanisms leading to the anti-metastatic properties of LTF in RCC cells.…”

“…However, RCC patients treated with sunitinib eventually become resistant [10]. More recently, immunotherapy (alone or in combination with TKIs) and cabozantinib exhibited a relative higher objective response rate and have been recommended as the standard of care for first-line treatment in metastatic RCC [11]. Therefore, there is an urgent need to more effectively treat metastatic RCC.…”

Anti-Angiogenesis and Immunotherapy: Novel Paradigms to Envision Tailored Approaches in Renal Cell-Carcinoma

“…(Figure 2 Due to the dynamic plethora of therapeutic options available to date, it is critical to identify criteria driving personalized approaches. Indeed, real-life clinical practice faces the significant challenge of patient selection by tailoring a TKI-vs. ICI-based and mono-vs. combination-therapeutic strategy [46,97]. Currently, besides the obvious impact of clinical individual risk profiling and comorbidities potentially influencing the safety issues, the single decision-making tool is represented by the risk stratification considered by the regulatory agencies.…”