Profiling the inhibitory receptors LAG-3, TIM-3, and TIGIT in renal cell carcinoma reveals malignancy

AbstractA cutting edge therapy for future immuno-oncology is targeting a new series of inhibitory receptors (IRs): LAG-3, TIM-3, and TIGIT. Both immunogenomic analyses and diagnostic platforms to distinguish candidates and predict good responders to these IR-related agents are vital in clinical pathology. By applying an automated single-cell count for immunolabelled LAG-3, TIM-3, and TIGIT, we reveal that individual IR levels with exclusive domination in each tumour can serve as valid biomarkers for profiling human renal cell carcinoma (RCC). We uncover the immunogenomic landscape associated with individual IR levels in human RCC tumours with metastases in various organs and histological subtypes. We then externally validate our results and devise a workflow with optimal biomarker cut-offs for discriminating the LAG-3, TIM-3, and TIGIT tumour profiles. The discrimination of LAG-3, TIM-3, and TIGIT profiles in tumours may have a broad impact on investigations of immunotherapy responses after targeting a new series of IRs.

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Profiling the inhibitory receptors LAG-3, TIM-3, and TIGIT in renal cell carcinoma reveals malignancy

10.21203/rs.3.rs-55869/v1 ◽

2020 ◽

Author(s):

Kimiharu Takamatsu ◽

Nobuyuki Tanaka ◽

Kyohei Hakozaki ◽

Ryohei Takahashi ◽

Shuji Mikami ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Cell Count ◽

Single Cell ◽

Renal Cell ◽

Clinical Pathology ◽

Cutting Edge ◽

Inhibitory Receptors ◽

Histological Subtypes ◽

Human Renal Cell Carcinoma

Abstract A cutting edge therapy for future immuno-oncology is targeting a new series of inhibitory receptors (IRs): LAG-3, TIM-3, and TIGIT. Both immunogenomic analyses and diagnostic platforms to distinguish candidates and predict good responders to these IR-related agents are vital in clinical pathology. By applying an automated single-cell count for immunolabeled LAG-3, TIM-3, and TIGIT, we revealed that individual IR levels with exclusive domination in each tumour can be valid biomarkers for profiling human renal cell carcinoma (RCC). We uncovered the immunogenomic landscape associated with individual IR levels in human RCC tumours with metastases in various organs and histological subtypes. We then externally validated our results and devised a workflow with optimal biomarker cut-offs for discriminating the tumour profiles of LAG-3, TIM-3, and TIGIT. The discrimination of LAG-3, TIM-3, and TIGIT profiles in tumours may have a broad impact on investigations on immunotherapy responses after targeting a new series of IRs.

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Profiling antigen specificity concurrently with protein and mRNA quantification using high throughput single-cell multiomics reveal surprising similarities between bystander and tumor specific CD8+ tumor-infiltrating lymphocytes (TILs) in renal cell carcinoma (RCC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15014 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15014-e15014

Author(s):

Aaron Tyznik ◽

Yannick Simoni ◽

Shamin Li ◽

Summer Zhuang ◽

Evan Newell

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Single Cell ◽

Renal Cell ◽

Tumor Antigens ◽

Tumor Infiltrating Lymphocytes ◽

Gene Signature ◽

Antigen Specificity ◽

Human Renal Cell Carcinoma ◽

Functional Roles

e15014 Background: Recently, using human colorectal and lung cancer, we showed that CD8+ T cells infiltrating tumor tissue (TILs) are not only specific for tumor antigens, but are also composed of CD8+ TILs specific for cancer unrelated epitopes – called bystander – such as HCMV, EBV or flu epitopes. We also showed that the surface marker CD39 can be useful for discriminating bystander (CD39−) from tumor-specific (CD39+) CD8+ TILs (Simoni et al, Nature, 2018). Methods: Here, our aim was to test these findings in human Renal cell Carcinoma (RCC) and to better understand the biology of these bystander CD8+ TILs. Results: Surprisingly, our primary CYTOF analyses showed heterogeneity within bystander CD8 TILs that possess various phenotypes including effector (CD45RO+), memory (CD45RO+ CCR7+), Trm (CD69+ CD103+/–), and senescent (CD57+ KLRG1+) cell features. Using targeted mRNA single-cell sequencing combined with BD AbSeq assay, we analyzed sorted CD8+ TILs from RCC patients and identified bystander CD8+ TILs using oligo-tagged tetramers. Gene signature analysis of these different subsets revealed transcriptomic similarities with the tumor-specific CD8+ TILs. Conclusions: Our data provide a comprehensive perspective of cancer unrelated CD8+ TILs in RCC and suggest functional roles for these cells in tumor immune responses, which could lead to new diagnostic and therapeutic strategies.

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