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

Although immune therapy can improve the treatment of clear cell renal cell carcinoma (ccRCC) significantly, there are still a large proportion of ccRCC patients who progress to metastasis. Targeting the pro-metastatic immune cell in the ccRCC microenvironment could provide a solution to this problem. In this study, B cells in ccRCC biopsies were identified by using scRNA-seq and flow cytometry. The findings indicated the presence of a pro-metastatic B cell type which could be further classified into 3 subpopulations, MARCH3, B2M and DTWD1, based on their large-scaled genetic profiles, rather than traditional Immature/Mature ones. Although all of the 3 subpopulations appeared to contribute to distant metastasis, B cell (B2M) was deemed to be the most essential. Moreover, STX16, CLASRP, ATIC, ACIN1 and SEMA4B, were genes found to be commonly up-regulated in the 3 subpopulations and this was correlated to a poor prognosis of ccRCC. Furthermore, the heterogeneity of plasma cells in ccRCC was also found to contribute to metastasis of the disease. This study offers potential novel therapeutic targets against distant metastasis of cancers, and can help to improve the therapeutic efficiency of ccRCC patients.

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Quantifying T- and B-cell immune receptor distribution diversity to uncover their clinical relevance in clear cell renal cell carcinoma

10.1101/2021.06.15.21258987 ◽

2021 ◽

Author(s):

Meghan C Ferrall-Fairbanks ◽

Nicholas Chakiryan ◽

Boris I Chobrutskiy ◽

Youngchul Kim ◽

Jamie K Teer ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

B Cell ◽

Cell Carcinoma ◽

Renal Cell ◽

Immune Cell ◽

Clear Cell ◽

Immune Microenvironment ◽

Cell Renal Cell Carcinoma ◽

Cdr3 Sequence ◽

Sequence Distributions

Immune-modulating systemic therapies are often used to treat 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 used complementarity determining region-3 (CDR3) sequence recovery counts of the tumor infiltrating lymphocytes, and quantified tumor infiltration by sequences recovered from patient tumors by applying a generalized diversity index (GDI) to CDR3 sequence distributions across two distinct ccRCC cohorts. GDI can be understood as a curve over a continuum of diversity scales and allows sensitive characterization of distributions to capture richness, evenness, and subsampling uncertainty, along with other important metrics. For example, richness quantifies the total unique sequence count, while evenness quantifies similarities across sequence frequencies. We observed significant differences in receptor sequence diversity across gender and race. Further, our analysis 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. We identified a novel and robust measure of distribution evenness, using GDI's inflection point (IP). High IP values associated with improved overall survival, suggesting that normal-like sequence distributions lead to better outcomes. Our results propose a new quantitative tool that can be used to better characterize patient-level differences related to immune cell infiltration and, can be used to identify unique characteristics of tumor-infiltrating lymphocyte heterogeneity in ccRCC and other malignancies.

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