Ferrall-Fairbanks’ paper accepted by Cancer Research

Clear cell renal cell carcinoma is characterized by an immunologically complex tumor microenvironment -- with a favorable response profile to checkpoint blockade but paradoxically negative clinical outcomes associated with high levels of tumor infiltrating lymphocytes. Herein, tumor infiltrating T and B-cell receptor hypervariable regions were characterized using a novel framework for diversity index classification, uncovering a strong association between T-cell receptor sequence distribution and overall survival. The cover shows an image of a human clear cell renal cell carcinoma tumor stained for DAPI (dark blue, nuclei), pan-cytokeratin (cyan; tumor cells), and CD8+ (yellow; cytotoxic T-cells).

Congratulations to Meghan Ferrall-Fairbanks, Ph.D., assistant professor, for having a collaborative group paper accepted in Cancer Research titled, Quantification of T- and B-cell immune receptor distribution diversity characterizes immune cell infiltration and lymphocyte heterogeneity in clear cell renal cell carcinoma.

The collaborative team from the University of Florida, H. Lee Moffitt Cancer Center, University of South Florida, and Max Planck Institute for Evolutionary Biology quantified tumor immune infiltration across the adaptive immune repertoire across three independent cohorts linking tumor immune ecology with tumor burden, aggressiveness, and patient survival.

Renal cell carcinoma ranks seventh and tenth among the most diagnosed cancers among men and women in the US. The most common type of renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). The arrival of immune checkpoint inhibitors (ICIs) has precipitated a tremendous research effort aiming to accurately characterize the tumor-immune microenvironment and explore potential biomarkers to predict ICI response, for which robust markers have mainly been elusive. Most investigations have focused on tumor-centric variables, including somatic mutations and gene expression. Fewer studies have focused on host factors that contribute to the microenvironment or how differences among these factors may affect clinical or therapeutic outcomes.

The team hypothesized that immune cell receptor sequence diversity recapitulates important features of tumor biology such as origin, environment-driven evolution, and progression risk. The work leverages properties of a generalized diversity index, a measure developed for the evolutionary theory of ecology, to quantify CDR3 sequence diversity, and assess how point estimates of this diversity metric associate with important clinicopathologic outcomes in ccRCC. The team finds that different point estimates give unique information about the tumor: increased richness was associated with the size and aggressiveness of a tumor, while dominance of the most abundant sequence was associated with poor prognosis.

Using these diversity metrics, the team identified a new approach to stratify renal cell carcinoma patients based on differences in immune infiltration diversity and further guide precision oncology. These novel objective metrics can provide insight into the underlying tumor and host immune relationships by defining differences within and across patients in renal cell carcinoma and this approach is more broadly applicable to other solid tumors. The ultimate goal of this research is to use tumor heterogeneity’s ecological and evolutionary impact to inform treatment decisions and improve responses to therapy.