Quantification of T- and B-cell immune receptor distribution diversity characterizes immune cell infiltration and lymphocyte heterogeneity in clear cell renal cell carcinoma.

Immune-modulating systemic therapies are often used to treat advanced cancer such as metastatic clear cell renal cell carcinoma (ccRCC). Used alone, sequence-based biomarkers neither accurately capture patient dynamics nor the tumor immune microenvironment.

To better understand the tumor ecology of this immune microenvironment, we quantified tumor infiltration across two distinct ccRCC patient tumor cohorts using complementarity determining region-3 (CDR3) sequence recovery counts in tumor-infiltrating lymphocytes and a generalized diversity index (GDI) for CDR3 sequence distributions. GDI can be understood as a curve over a continuum of diversity scales which allows sensitive characterization of distributions to capture sample richness, evenness, and subsampling uncertainty, along with other important metrics that characterize tumor heterogeneity. For example, richness quantified the total unique sequence count, while evenness quantified similarities across sequence frequencies. Significant differences in receptor sequence diversity across gender and race revealed that patients with larger and more clinically aggressive tumors had increased richness of recovered tumoral CDR3 sequences, specifically in those from T-cell receptor alpha and B-cell immunoglobulin lambda light chain. The GDI inflection point (IP) allowed for a novel and robust measure of distribution evenness. High IP values associated with improved overall survival, suggesting that normal-like sequence distributions lead to better outcomes. These results propose a new quantitative tool that can be used to better characterize patient-specific differences related to immune cell infiltration, and to identify unique characteristics of tumor-infiltrating lymphocyte heterogeneity in ccRCC and other malignancies.

Cancer research. 2022 Jan 14 [Epub ahead of print]

Meghan C Ferrall-Fairbanks, Nicholas Chakiryan, Boris I Chobrutskiy, Youngchul Kim, Jamie K Teer, Anders Berglund, James J Mulé, Michelle Fournier, Erin M Siegel, Jasreman Dhillon, Seyed Shayan Ahmad Falasiri, Juan F Arturo, Esther N Katende, George Blanck, Brandon J Manley, Philipp M Altrock

J. Crayton Pruitt Family Department of Biomedical Engineering, State University System of Florida., Genitourinary Oncology, Moffitt Cancer Center., Molecular Medicine, University of South Florida., Department of Biostatistics and Bioinformatics, Moffitt Cancer Center., Biostatistics and Bioinformatics, Moffitt Cancer Center., Department of Biostatistics and Bioinformatics, Division of Population Sciences, H. Lee Moffitt Cancer Center & Research Institute., Cutaneous Oncology, Moffitt Cancer Center., Tissue Core Administration, Moffitt Cancer Center., Cancer Epidemiology Program, Division of Population Sciences, H. Lee Moffitt Cancer Center & Research Institute., Department of Anatomic Pathology, Moffitt Cancer Center., Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute., University of South Florida., Molecular Medicine, University of South Florida Morsani College of Medicine., Department of Evolutionary Theory, Max Planck Institute for Evolutionary Biology .

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