The Identification of Immunological Biomarkers in Kidney Cancers

Abstract

The recent approval of several agents have revolutionized the scenario of therapeutic management of metastatic renal cell carcinoma (RCC) allowing us to reach important clinical end points with extended patients' survival. Actually, every new drug approved has represented an important step forward to the improvement of patient's survival. On the other hand, we now understand that RCC includes a large group of tumor entities, each of them with different genetic and mutational alterations, but also showing different clinical behavior; a reason behind the needs of subtype specific personalized approach to therapy of RCC. Immunotherapy is gradually becoming a key factor in the therapeutic algorithm for patients with locally advanced or metastatic RCC. Due to the combination of potent treatment success and potentially deadly adverse effects from immune checkpoint inhibitors (ICI), gathering prognostic and predictive information about FDA-indicated tumors seems to be prudent. Robust and reliable biomarkers are crucial for patient's selection of treatments with immunomodulatory drugs. PD-L1 expression is a poor prognostic factor and predictive of better responses from both PD-1 and PD-L1 inhibitors in a variety of tumor types including RCC. Each FDA approved PD-1/PD-L1 drug is paired with a PD-L1 Immunohistochemistry (IHC) assay. Thus, there is need for improved knowledge and application of PD-1/PD-L1 IHC biomarkers in daily practice. IHC staining appears in membranous fashion. The atezolizumab approved IHC assay is unique in that only immune cell staining is quantified for the use of this assay in RCC. A single biomarker for patient selection may not be feasible, given that immune responses are dynamic and evolve over time. Biomarker development for ICI drugs will likely require integration of multiple biologic components like PD-L1 expression, TILs and mutational load. New methodological approaches based on digital pathology may be relevant since they will allow recognition of the biomarker and to objectively quantitate its expression, and therefore might produce objective and reproducible cut-off assessment. Multidisciplinary approach is very much needed to fully develop the current and future value of ICI in clinical practice.

Modeling clear cell renal cell carcinoma and therapeutic implications

“…Additionally, for patients who initially respond, many will progress while on treatment as tumor cells develop resistance 49 , 51 . Ongoing efforts seek to identify and confirm clinically relevant predictive biomarkers in ccRCC to aid clinicians in immunotherapy selection 52 , 53 . As such, model systems capable of recapitulating the TME are crucial to enhance our understanding of drug interactions.…”

Claspin overexpression is associated with high‐grade histology and poor prognosis in renal cell carcinoma

“…The prognosis of advanced RCC is poor in part because RCC is often resistant to traditional therapies such as radiation therapy and chemotherapy. Epidermal growth factor receptor‐tyrosine kinase inhibitors and immunocheckpoint inhibitors targeting PD‐1 or its ligand PD‐L1 showed promising therapeutic efficacy in advanced RCC . Recent reports showed that the expression of EGFR and PD‐L1 is a poor prognostic factor in RCC .…”

“…Epidermal growth factor receptor-tyrosine kinase inhibitors and immunocheckpoint inhibitors targeting PD-1 or its ligand PD-L1 showed promising therapeutic efficacy in advanced RCC. [3][4][5][6][7] Recent reports showed that the expression of EGFR and PD-L1 is a poor prognostic factor in RCC. 6-8 Prognostic biomarkers are important in the guidance of therapeutic options and…”

Concordance of PD‐1 and PD‐L1 (B7‐H1) in paired primary and metastatic clear cell renal cell carcinoma

“…While immune checkpoint inhibitors have been successful in advanced ccRCC patients, not all patients respond to these inhibitors. Thus, there is an important clinical need to identify biomarkers for these promising therapies . Related to this, while higher PD‐1 and PD‐L1 expressions in primary tumors have shown to predict poor survival, their role in selecting patients for immune checkpoint inhibitors remains unclear .…”