Quantification of T- and B-cell Immune Receptor Distribution Diversity Characterizes Immune Cell Infiltration and Lymphocyte Heterogeneity in Clear Cell Renal Cell Carcinoma

Author:

Ferrall-Fairbanks Meghan C.123ORCID,Chakiryan Nicholas H.4,Chobrutskiy Boris I.5,Kim Youngchul6ORCID,Teer Jamie K.6ORCID,Berglund Anders6ORCID,Mulé James J.7ORCID,Fournier Michelle4,Siegel Erin M.8ORCID,Dhillon Jasreman9,Falasiri Seyed Shayan A.5ORCID,Arturo Juan F.5,Katende Esther N.4ORCID,Blanck George57,Manley Brandon J.14ORCID,Altrock Philipp M.110ORCID

Affiliation:

1. 1Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, Florida.

2. 2J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida.

3. 3University of Florida Health Cancer Center, University of Florida, Gainesville, Florida.

4. 4Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, Florida.

5. 5Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida.

6. 6Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida.

7. 7Department of Immuno Oncology, Moffitt Cancer Center, Tampa, Florida.

8. 8Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida.

9. 9Department of Pathology, Moffitt Cancer Center, Tampa, Florida.

10. 10Department of Evolutionary Theory, Max Planck Institute for Evolutionary Biology, Ploen, Germany.

Abstract

Abstract 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 three 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 that 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 were 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. Significance: Assessment of tumor-infiltrating T-cell and B-cell diversity in renal cell carcinoma advances the understanding of tumor-immune system interactions, linking tumor immune ecology with tumor burden, aggressiveness, and patient survival. See related commentary by Krishna and Hakimi, p. 764

Funder

H. Lee Moffitt Cancer Center & Research Institute

U.S. Army Medical Research Acquisition Activity Department of Defense

William G. ‘Bill’ Bankhead Jr and David Coley Cancer Research Program

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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