BackgroundTumor-infiltrating immune cells have been linked to prognosis and response to immunotherapy; however, the levels of distinct immune cell subsets and the signals that draw them into a tumor, such as the expression of antigen presenting machinery genes, remain poorly characterized. Here, we employ a gene expression-based computational method to profile the infiltration levels of 24 immune cell populations in 19 cancer types.ResultsWe compare cancer types using an immune infiltration score and a T cell infiltration score and find that clear cell renal cell carcinoma (ccRCC) is among the highest for both scores. Using immune infiltration profiles as well as transcriptomic and proteomic datasets, we characterize three groups of ccRCC tumors: T cell enriched, heterogeneously infiltrated, and non-infiltrated. We observe that the immunogenicity of ccRCC tumors cannot be explained by mutation load or neo-antigen load, but is highly correlated with MHC class I antigen presenting machinery expression (APM). We explore the prognostic value of distinct T cell subsets and show in two cohorts that Th17 cells and CD8+ T/Treg ratio are associated with improved survival, whereas Th2 cells and Tregs are associated with negative outcomes. Investigation of the association of immune infiltration patterns with the subclonal architecture of tumors shows that both APM and T cell levels are negatively associated with subclone number.ConclusionsOur analysis sheds light on the immune infiltration patterns of 19 human cancers and unravels mRNA signatures with prognostic utility and immunotherapeutic biomarker potential in ccRCC.

Additional file 1: Figures S1â S25. of Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures

Abstract Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephrectomy for high-risk, non-metastatic clear cell renal cell carcinoma (ccRCC). We conducted a prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from that cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response. We found that nivolumab durably induces a pro-inflammatory state within the primary tumor, and baseline immune infiltration within the primary tumor correlates with nivolumab responsiveness. Nivolumab increases CTLA-4 expression in the primary tumor, and subsequent nephrectomy increases circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. These findings form the basis to consider neoadjuvant immune checkpoint inhibition (ICI) for high-risk ccRCC while the tumor remains in situ and provide the rationale for perioperative strategies of novel ICI combinations. 

Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma

Simple Summary Receptor tyrosine kinases are essential for the development, growth, and progression of clear cell renal cell carcinoma (ccRCC). Targeted therapies using receptor tyrosine kinase inhibitors are widely used in ccRCC treatment. Myoferlin is a well-known protein that regulates various receptor tyrosine kinases. We aimed to identify myoferlin-associated receptor tyrosine kinases and their prognostic implications in ccRCC. After screening with proteomic analysis, we focused on c-Met and EPHA7 receptor tyrosine kinases. c-Met expression was associated with poor prognosis in ccRCC, and there was an indication that the c-Met pathway may be regulated by myoferlin. Although the expression of EPHA7 and myoferlin was not corelated, the expression of EPHA7 was also associated with unfavorable outcomes. These results suggest that c-Met and EPHA7 might be useful prognostic biomarkers, and the presumed myoferlin/c-Met pathway could be a novel therapeutic target in ccRCC. Abstract Receptor tyrosine kinases (RTKs) are important targets for clear cell renal cell carcinoma (ccRCC) treatment. Myoferlin is a strong regulator of RTKs. To identify myoferlin-associated RTKs and their prognostic implications in ccRCC, we investigated the expression of RTKs and myoferlin using proteome-based evaluation and immunohistochemical staining in tissue microarray. Multivariate Cox analysis adjusted for TNM stage and WHO grade was performed (n = 410 and 506). Proteomic analysis suggested c-Met and EPHA7 as novel candidates for myoferlin-associated RTKs. We immunohistochemically validated the positive association between c-Met and myoferlin expression. High c-Met expression was independently associated with overall (hazard ratio (HR) = 1.153–2.919) and cancer-specific survival (HR = 1.150–3.389). The prognostic effect of high c-Met expression was also determined in an independent cohort (overall survival, HR = 1.503–3.771). Although expression of EPHA7 and myoferlin was not correlated, EPHA7 expression was independently associated with progression-free (HR = 1.237–4.319) and cancer-specific survival (HR = 1.214–4.558). In addition, network-based prioritization showed co-functional enrichment of c-Met and myoferlin, suggesting a novel regulatory function of myoferlin in c-Met signaling. This study indicates that c-Met and EPHA7 might be useful prognostic biomarkers, and the presumed myoferlin/c-Met pathway could be a novel therapeutic target in ccRCC.

/pdf/c-met-and-epha7-receptor-tyrosine-kinases-are-related-to-202qshzm.pdf

c-Met and EPHA7 Receptor Tyrosine Kinases Are Related to Prognosis in Clear Cell Renal Cell Carcinoma: Focusing on the Association with Myoferlin Expression

Advances in understanding the mechanisms of tumour-induced immunosuppression have led to the development of immune-checkpoint inhibitors in cancer patients, including those with renal cell carcinoma (RCC). The optimal combination between immunotherapy and targeted agents (as well as the possible favourable sequential therapy of these two classes of drugs) remains an open question at this moment. Several trials are currently underway to assess the combination of anti-programmed-death 1 (PD-1) or anti-PD-ligand(L)1 agents with other immunotherapies or with anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). In this editorial, we described the results of the most recent clinical trials on the use of immunotherapies in RCC and the emerging data on the research for reliable biomarkers of tumour response in this setting. In addition, we have focused on the role of the gut microbiome and tumour microenvironment in the development of future therapeutic strategies for RCC patients.

Immunotherapy in renal cell carcinoma: latest evidence and clinical implications


 
 
 The prognosis of clear cell renal cell carcinoma (ccRCC) is typically based on clinical stage, but it can vary for some patients. Transcriptomic analysis is vital for understanding ccRCC progression, though its correlation with the clinical stage in predicting prognosis is uncertain. We aim to employ trajectory inference to study ccRCC’s molecular progression and identify potential new markers for judging disease progression and prognosis.
 
 
 
 Using a trajectory inference approach, we characterize the molecular progression profile of ccRCC based on transcriptome profiling. Additional pathway activity, immune response, and miRNA profiling scoring were integrated to identify possible drivers of trajectory progression.
 
 
 
 Scoring based on the trajectory demonstrates a significant improvement in patient prognosis prediction and identifies 10 risk factors in patients with low-grade tumors, and nine protective factors in patients with high-grade tumors. Mechanistically, we demonstrate an association between solute light carrier transporters are associated with ccRCC progression, with SLC7A5 expression being validated through immunohistochemistry to increase in metastatic patients.
 
 
 
 Trajectory analysis of ccRCC transcriptomes can be used to model the molecular progression of disease and may assist in ccRCC prognosis. SLC7A5 is aberrantly expressed in ccRCC and may be a risk factor for poor prognosis.


Trajectory mapping of renal clear cell carcinoma transcriptomes identifies stage-independent predictors of favorable prognosis

High-dimensional Cytometry (ExCYT) and Mass Spectrometry of Myeloid Infiltrate in Clinically Localized Clear Cell Renal Cell Carcinoma Identifies Novel Potential Myeloid Targets for Immunotherapy.

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High-dimensional Cytometry (ExCYT) and Mass Spectrometry of Myeloid Infiltrate in Clinically Localized Clear Cell Renal Cell Carcinoma Identifies Novel Potential Myeloid Targets for Immunotherapy.