Predicted CD4+ T cell infiltration levels could indicate better overall survival in sarcoma patients

Objective The role of tumor-infiltrating lymphocytes (TILs) has not yet been characterized in sarcomas. The aim of this bioinformatics study was to explore the effect of TILs on sarcoma survival and genome alterations. Methods Whole-exome sequencing, transcriptome sequencing, and survival data of sarcoma were obtained from The Cancer Genome Atlas. Immune infiltration scores were calculated using the Tumor Immune Estimation Resource. Potential associations between abundance of infiltrating TILs and survival or genome alterations were examined. Results Levels of CD4+ T cell infiltration were associated with overall survival of patients with pan-sarcomas, and higher CD4+ T cell infiltration levels were associated with better survival. Somatic copy number alterations, rather than mutations, were found to correlate with CD4+ T cell infiltration levels. Conclusions This data mining study indicated that CD4+ T cell infiltration levels predicted from RNA sequencing could predict sarcoma prognosis, and higher levels of CD4+ T cells infiltration indicated a better chance of survival.

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88 Development of a 3D organoid autologous TIL co-culture platform for high throughput immuno-oncology studies

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0088 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A98-A98

Author(s):

Garima Kaushik ◽

Bhavna Verma ◽

Amy Wesa

Keyword(s):

T Cell ◽

High Throughput ◽

Fluorescent Dyes ◽

Tumor Infiltrating Lymphocytes ◽

Cell Infiltration ◽

Patient Specific ◽

T Cell Infiltration ◽

Organoid Cultures ◽

Infiltrating Lymphocytes

BackgroundThe preclinical screening of immune-modulatory therapies suffers from the absence of models that recapitulate in vivo heterogeneous tumor microenvironment (TME). 3D tumor organoid cultures provide a model that closely mimics in situ tumor architecture and is being aggressively used to evaluate therapeutic efficacy ex vivo. A vastly heterogenous TME impacts patient treatment response, and there is a dearth of human tumor models (2D or 3D), that mimic in vivo diversity of TME, including infiltrating immune populations. 3D organoid cultures typically contain neoplastic epithelium; however, they fall short in representing tumor to tumor-infiltrating lymphocytes (TILs) interactions, limiting their ability to generate a clinically relevant response to immunotherapeutics. Addition of immune cells from unrelated donors to organoids can simulate that microenvironment but is complicated by T cell alloreactivity. Here we describe 3D patient-derived xenograft organoid (PDXO) co-cultures with matching autologous human TILs to recapitulate the tumor-specific immune response, leveraging confocal high content analysis and luminex multiplex assays. This platform allows the evaluation and high throughput screening of novel immune targeting agents to determine impacts on patient-derived T cell function, T cell infiltration, and tumor cytotoxicity.MethodsSurgical resections from patients were used to generate patient-derived xenografts and tumor-infiltrating lymphocytes in parallel. PDX were resected and digested to establish PDXO. TILs and organoids from the same patient were fluorescent labeled and cultured together for four days to evaluate tumor infiltration and drug cytotoxicity in 3D cultures. CellInsight CX7 high content imaging platform was used to trace TILs and cancer cells and evaluate T cell infiltration and tumor cell killing in the presence and absence of immuno-modulatory therapies.ResultsPDXO were established to mimic in vivo tumor biology. Tumor-specific TILs were successfully expanded and characterized by flow cytometry. Co-culture resulted in TIL infiltration in organoids from day one in culture and increased over four days. Cytotoxicity and TIL infiltration were quantified using fluorescent dyes via high throughput imaging platform. Significantly enhanced TIL infiltration was observed in autologous co-cultures compared to non-autologous co-cultures. The established unique autologous PDXO immune organoid co-cultures could be used as an improved simulation of the modulatory activity of therapeutic agents in patient-specific T cells against their own tumors.ConclusionsPatient autologous TILs – PDXO co-culture platform is an advanced model for evaluating IO therapeutics with the tumor-specific immune microenvironment. The platform provides an opportunity for precision medicine and high throughput drug screening of immuno-modulatory therapies.Ethics ApprovalThe study was approved by Champions Oncology’s Institutional Animal Care and Use Committee (IACUC).

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Low expression of NSD1, NSD2, and NSD3 define a subset of human papillomavirus-positive oral squamous carcinomas with unfavorable prognosis

Infectious Agents and Cancer ◽

10.1186/s13027-021-00347-6 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Steven F. Gameiro ◽

Farhad Ghasemi ◽

Peter Y. F. Zeng ◽

Neil Mundi ◽

Christopher J. Howlett ◽

...

Keyword(s):

Human Papillomavirus ◽

T Cell ◽

The Cancer Genome Atlas ◽

Cell Infiltration ◽

Relative Level ◽

Expression Levels ◽

T Cell Infiltration ◽

Molecular Features ◽

Platinum Based Chemotherapy ◽

Low Expression

Abstract Background Frequent mutations in the nuclear receptor binding SET domain protein 1 (NSD1) gene have been observed in head and neck squamous cell carcinomas (HNSCC). NSD1 encodes a histone 3 lysine-36 methyltransferase. NSD1 mutations are correlated with improved clinical outcomes and increased sensitivity to platinum-based chemotherapy agents in human papillomavirus-negative (HPV-) tumors, despite weak T-cell infiltration. However, the role of NSD1 and related family members NSD2 and NSD3 in human papillomavirus-positive (HPV+) HNSCC is unclear. Methods Using data from over 500 HNSCC patients from The Cancer Genome Atlas (TCGA), we compared the relative level of mRNA expression of NSD1, NSD2, and NSD3 in HPV+ and HPV- HNSCC. Correlation analyses were performed between T-cell infiltration and the relative level of expression of NSD1, NSD2, and NSD3 mRNA in HPV+ and HPV- HNSCC. In addition, overall survival outcomes were compared for both the HPV+ and HPV- subsets of patients based on stratification by NSD1, NSD2, and NSD3 expression levels. Results Expression levels of NSD1, NSD2 or NSD3 were not correlated with altered lymphocyte infiltration in HPV+ HNSCC. More importantly, low expression of NSD1, NSD2, or NSD3 correlated with significantly reduced overall patient survival in HPV+, but not HPV- HNSCC. Conclusion These results starkly illustrate the contrast in molecular features between HPV+ and HPV- HNSCC tumors and suggest that NSD1, NSD2, and NSD3 expression levels should be further investigated as novel clinical metrics for improved prognostication and patient stratification in HPV+ HNSCC.

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Comparative Multiomic Analysis Reveals Low T Cell Infiltration as the Primary Feature of Tobacco Use in HPV(+) Oropharyngeal Cancer

10.1101/2021.03.23.436478 ◽

2021 ◽

Author(s):

Benjamin M Wahle ◽

Paul Zolkind ◽

Ricardo Ramirez ◽

Zachary L Skidmore ◽

Angela Mazul ◽

...

Keyword(s):

T Cell ◽

Tobacco Use ◽

Disease Free Survival ◽

Oncologic Outcomes ◽

Cell Infiltration ◽

Tobacco Exposure ◽

Primary Tumors ◽

T Cell Infiltration ◽

Mutational Burden ◽

Whole Exome

Purpose: Tobacco use is an independent adverse prognostic feature in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Despite this, the biologic features associated with tobacco use have not been systematically investigated in this population. We sought to characterize the genomic and immunologic features of HPV(+) OPSCC associated with tobacco use and adverse oncologic outcomes. Experimental Design: Whole exome sequencing of 47 primary HPV(+) OPSCC tumors was performed to investigate mutational differences associated with tobacco exposure. To characterize the tumor immune microenvironment (TIME), targeted mRNA hybridization was performed and immunohistochemical (IHC) staining was used to validate these findings. Results: Low expression of transcripts in a T cell-inflamed gene expression profile (TGEP) was associated with tobacco use at the time of diagnosis and lower overall and disease-free survival. Tobacco use was associated with an increased proportion of T>C substitutions and a lower proportion of mutational signatures typically observed in HPV(+) OPSCC tumors, but was not associated with increases in mutational burden or the rate of recurrent oncogenic mutations. Conclusions: In HPV(+) OPSCC, low T cell infiltration of primary tumors is associated with current tobacco use and worse oncologic outcomes. Rather than an increased mutational burden, tobacco's primary and clinically relevant association is immunosuppression of the primary TIME. An objective clinical assay like the TGEP, which quantifies immune infiltration of the primary TIME, may have value for HPV(+) OPSCC risk stratification in future clinical trials.

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Identification of predictive biomarker for immunotherapy by associating with CD8+T cell Infiltration in lung adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21177 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21177-e21177

Author(s):

Puyuan Xing ◽

Teng Li ◽

Han Wang ◽

Lin Yang ◽

Guoqiang Wang ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Predictive Biomarkers ◽

Tumor Infiltrating Lymphocytes ◽

Predictive Performance ◽

Predictive Biomarker ◽

Pooled Analysis ◽

The Cancer Genome Atlas ◽

T Cell Infiltration ◽

Or Groups ◽

Cancer Genome Atlas

e21177 Background: Tumor immune microenvironment (TIME) has been proved associated with response to immunotherapy(I/O). We hypothesized that screening potential mutation pattern which could significantly impact the tumor infiltrating lymphocytes(TILs) can help us to identify predictive biomarkers for I/O in Lung adenocarcinoma(LUAD). Methods: Multiple-dimensional data from The Cancer Genome Atlas LUAD cohort (n = 514) was used for building a mathematical model beween mutation signature and CD8+TIL score (based on MCP-counter). An independent public validation cohort (cohort 1: LUAD, n = 598) were used to assess the immunotherapeutic predictive performance of the potential mutation patterns. Results: Top 100 gene associated with CD8+TIL score were selected based on MC+ model which can provides the minimum non-convexity of the penalized loss given the level of bias. Seven TIME genes (SPTA1 coef 0.09; MET coef 0.02; HSD3B1 coef -0.00; STAT4 coef -0.01; EGFR coef -0.08; PIK3CB coef -0.08; KEAP1 coef -0.24) were generated by taking the intersection of the top 100 mutant genes and FoundationOne (F1) CDx NGS 315 genes panel and verified in cohort 1. Survival analysis showed that SPTA1mt was the only one that associated with both significantly longer PFS (median PFS 3.15 vs 2.89 months; HR 0.65; 95% CI 0.45 to 0.93; p = 0.02) and OS (median PFS 15.08 vs 7.36 months; HR 0.59; 95% CI 0.40 to 0.88; p = 0.01) for patients who received I/O compared with chemotherapy(CT) among seven TIME genes. In order to test our hypothesis fully, a pooled analysis of SPTA1mt (a core positive predictors of CD8+TILs) and KEAP1mt (a core negative predictors for CD8+TILs ) were conducted and yielded that co occurrence of SPTA1mt and KEAP1mt had a compound effects for TIME. The validation showed that co mutation with SPTA1mt was accompanied by an decrease HR for I/O vs. CT in both PFS (HR S+K vs. K only 0.59 vs 1.56) and OS (HR S+K vs. K only 0.39 vs 0.80) for KEAP1mt patients. Conclusions: Our data show that it is feasible to identify individuals or groups of individual with specific mutations to immunotherapy responses from TIME view. SPTA1mt was a core predictors for higher CD8+ TILs and can be identified as a predictive biomarker for benefit from I/O compared with CT. Prospective studies are warranted for further investigation.

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Predicting CD8+ T-cell infiltration in colorectal cancer using versican proteolysis across molecular profiles.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.189 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 189-189

Author(s):

Katherine Anne Johnson ◽

Philip Emmerich ◽

Kristina A. Matkowskyj ◽

Dustin A. Deming

Keyword(s):

Colorectal Cancer ◽

T Cell ◽

Tumor Infiltrating Lymphocytes ◽

Cd8 T Cell ◽

Cell Infiltration ◽

Molecular Profile ◽

High Power Field ◽

Kras Mutations ◽

T Cell Infiltration ◽

The Impact

189 Background: The clinical indications for immunotherapies continue to increase across cancer types. In colorectal cancer (CRC), there has been little progress in the use of these therapies outside of mismatch repair deficient cancers (dMMR). However, even in dMMR cancers only a minority actually respond to the FDA-approved anti-PD1 agents. The tumor microenvironment is increasingly implicated in the resistance of cancers to immune-based therapies. Our group has previously described that accumulation of a matrix proteoglycan, versican, correlates with a reduction in CD8+ T-cell infiltration in CRCs, while proteolysis of versican, releasing the bioactive fragment versikine, correlates with increased infiltration. Here we examine the impact of pathogenic mutations on the utility of MMR status and versican proteolysis to predict CD8+ T-cell infiltration. Methods: Matched normal colon and CRC tissues from 122 patients were stained for versican, versikine, MLH1, MSH2, MSH6, PMS2, CNNB1, and CD8. Each was reviewed by a blinded GI surgical pathologist and CD8 quantified as tumor infiltrating lymphocytes (TILs) per high power field (hpf). 107 of the CRC samples were available for sequencing using the Qiagen Comprehensive Cancer Panel examining 160 genes across cancer relevant hotspots. The molecular profile was correlated with the IHC staining. Results: As previously reported, dMMR tumors had higher CD8+ T-cell infiltration. This trend persisted across dMMR genotypes (dMMR vs proficient (p)MMR p = 0.0016). Versican proteolysis correlated with increased CD8+ T cell infiltration in dMMR and pMMR cancers and was present in cancers with/without APC, TP53, and KRAS mutations. Across common mutations, cancers with the versican proteolysis predominant phenotype had more CD8+ T-cell infiltration than those without (APC mutant (mt): 11.82 vs 1.97 CD8+ TILs/hpf, p < 0.001; KRAS mt: 9.39 vs 3.08, p = 0.15; BRAF mt: 25.00 vs 7.50, p = 0.13; TP53 mt: 8.61 vs 1.63, p < 0.001). Conclusions: Across common mutations, versican proteolysis predicts CD8+ T-cell infiltration in both dMMR and pMMR CRC. Further investigation into whether this increase in infiltration will lead to greater immunotherapy response is warranted.

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Spatial heterogeneity and organization of tumor mutation burden and immune infiltrates within tumors based on whole slide images correlated with patient survival in bladder cancer

10.1101/554527 ◽

2019 ◽

Cited By ~ 5

Author(s):

Hongming Xu ◽

Sunho Park ◽

Jean René Clemenceau ◽

Jinhwan Choi ◽

Nathan Radakovich ◽

...

Keyword(s):

Bladder Cancer ◽

Spatial Heterogeneity ◽

Tumor Cells ◽

Tumor Infiltrating Lymphocytes ◽

The Cancer Genome Atlas ◽

Mutation Burden ◽

Prognostic Utility ◽

Cancer Genome Atlas ◽

Infiltrating Lymphocytes ◽

Whole Slide Images

AbstractHigh-TMB (TMB-H) could result in an increased number of neoepitopes from somatic mutations expressed by a patient’s own tumor cell which can be recognized and targeted by neighboring tumor-infiltrating lymphocytes (TILs). Deeper understanding of spatial heterogeneity and organization of tumor cells and their neighboring immune infiltrates within tumors could provide new insights into tumor progression and treatment response. Here we developed and applied computational approaches using digital whole slide images (WSIs) to investigate spatial heterogeneity and organization of regions harboring TMB-H tumor cells and TILs within tumors, and its prognostic utility. In experiments using WSIs from The Cancer Genome Atlas bladder cancer (BLCA), our findings show that WSI-based approaches can reliably predict patient-level TMB status and delineate spatial TMB heterogeneity and co-organization with TILs. TMB-H patients with low spatial heterogeneity enriched with high TILs show improved overall survival indicating a prognostic role of spatial TMB and TILs information in BLCA.

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Comprehensive analysis of PD-L1 expression, tumor-infiltrating lymphocytes, and tumor microenvironment in LUAD: differences between Asians and Caucasians

Clinical Epigenetics ◽

10.1186/s13148-021-01221-3 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Fenglong Bie ◽

He Tian ◽

Nan Sun ◽

Ruochuan Zang ◽

Moyan Zhang ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Infiltrating Lymphocytes ◽

The Cancer Genome Atlas ◽

Normal Tissues ◽

Asian Patients ◽

Expression Of Genes ◽

Tumor Tissues ◽

Significant Difference ◽

Cancer Genome Atlas ◽

Infiltrating Lymphocytes

Abstract Backgrounds The characteristics of programmed cell death protein-1 (PD-L1) expression, tumor-infiltrating lymphocytes (TILs), and tumor microenvironment (TME) in lung adenocarcinoma (LUAD) patients are closely related to immunotherapy, and there are differences between Asians and Caucasians. Methods Acquire the transcriptome data of the Cancer Genome Atlas and Chinese LUAD patients. R software was used to analyze the differential expression of genes, prognosis, and gene function. Use CIBERSORT for TIL-related analysis and ESTIMATE for TME-related analysis. Results The expression of PD-L1 in tumor tissues of Caucasian LUAD patients was lower than that in normal tissues, while there was no significant difference in Asians. There was no statistical difference between PD-L1 expression and prognosis. The composition of TILs between Caucasian and Asian LUAD patients was quite different. There was no correlation between TILs and prognosis in Caucasians. However, the higher content of resting mast cells indicated a better prognosis in Asians. The Caucasian patients with higher immune and estimate scores had a better prognosis (p = 0.021, p = 0.025). However, the Asian patients with a higher estimate score had a worse prognosis (p = 0.024). The high expression of COL5A2 (p = 0.046, p = 0.027) and NOX4 (p = 0.020, p = 0.019) were both associated with the poor prognosis in Caucasians and Asians. Conclusion There are many differences in the characteristics of PD-L1 expression, TILs, and TME between Caucasian and Asian LUAD patients. This provides a certain hint for the selection of specific immunotherapy strategies separately for Caucasian and Asian LUAD patients.

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Angiogenin Upregulation Independently Predicts Unfavorable Overall Survival in Proneural Subtype of Glioblastoma

Technology in Cancer Research & Treatment ◽

10.1177/1533033819846636 ◽

2019 ◽

Vol 18 ◽

pp. 153303381984663

Author(s):

Ji-liang Hu ◽

Wei-Jian Luo ◽

Hao Wang

Keyword(s):

Overall Survival ◽

Survival Data ◽

Cox Regression ◽

The Cancer Genome Atlas ◽

Isocitrate Dehydrogenase 1 ◽

Study Results ◽

Cancer Genome Atlas ◽

Secondary Study ◽

Independent Indicator ◽

Temozolomide Chemotherapy

Objective: Angiogenin is a small protein that exerts potent stimulating effects on angiogenesis. In this study, we aimed to examine the expression of angiogenin in different subtypes of glioblastoma and estimated its independent prognostic value. Methods: The genomic and survival data from The Cancer Genome Atlas-glioblastoma were extracted for a secondary study. Results The expression of angiogenin was upregulated in glioblastoma tissues and varied significantly in different subtypes. Although the proneural subtype had the lowest angiogenin expression, high angiogenin expression was associated with significantly worse overall survival. However, this association was not observed in other subtypes. By performing univariate and multivariate analysis using Cox regression model, we observed that high angiogenin expression was an independent indicator of shorter overall survival in proneural glioblastoma (hazard ratio: 1.669, 95% confidence interval: 1.033-2.696, P = .036), after adjustment of age, gender, isocitrate dehydrogenase 1 mutation, temozolomide chemotherapy and radiation therapy. In addition, we also observed a correlation between elevated angiogenin expression and the hypomethylated status of its DNA. The hypermethylation group had significantly better overall survival. Conclusions: Angiogenin upregulation might serve as a biomarker for unfavorable overall survival in the proneural subtype of glioblastoma.

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Cellular and gene signatures of tumor-infiltrating dendritic cells and natural-killer cells predict prognosis of neuroblastoma

Nature Communications ◽

10.1038/s41467-020-19781-y ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Ombretta Melaiu ◽

Marco Chierici ◽

Valeria Lucarini ◽

Giuseppe Jurman ◽

Libenzio Adrian Conti ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Nk Cells ◽

Natural Killer ◽

Tumor Infiltrating Lymphocytes ◽

Gene Signatures ◽

Protein Levels ◽

T Cell Infiltration ◽

Clinical Biomarkers ◽

Infiltrating Lymphocytes

AbstractTumor-infiltrating lymphocytes play an essential role in improving clinical outcome of neuroblastoma (NB) patients, but their relationship with other tumor-infiltrating immune cells in the T cell-inflamed tumors remains poorly investigated. Here we show that dendritic cells (DCs) and natural killer (NK) cells are positively correlated with T-cell infiltration in human NB, both at transcriptional and protein levels, and associate with a favorable prognosis. Multiplex imaging displays DC/NK/T cell conjugates in the tumor microenvironment of low-risk NB. Remarkably, this connection is further strengthened by the identification of gene signatures related to DCs and NK cells able to predict survival of NB patients and strongly correlate with the expression of PD-1 and PD-L1. In summary, our findings unveil a key prognostic role of DCs and NK cells and indicate their related gene signatures as promising tools for the identification of clinical biomarkers to better define risk stratification and survival of NB patients.

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Versican proteolysis as a key regulator of CD8+ T-cell infiltration in colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15082 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15082-e15082

Author(s):

Dustin A. Deming ◽

Chelsea Hope ◽

Philip Emmerich ◽

Adam Pagenkopf ◽

Kristina Matkowskyj ◽

...

Keyword(s):

Colorectal Cancer ◽

T Cell ◽

Mismatch Repair ◽

Tumor Infiltrating Lymphocytes ◽

Cd8 T Cell ◽

Staining Intensity ◽

Cell Infiltration ◽

Tissue Samples ◽

Tumor Bed ◽

T Cell Infiltration

e15082 Background: Colorectal cancer (CRC) originates within immunologically complex microenvironments. To date the benefits of immunotherapy have been modest except in neoantigen-laden mismatch repair (MMR)-deficient tumors. Approaches to enhance tumor-infiltrating lymphocytes (TILS) in the tumor bed may substantially augment clinical immunotherapy responses. Proteolysis of the tolerogenic matrix proteoglycan versican (VCAN) generates a bioactive fragment, versikine, with putative immunostimulatory activities. Methods: Matched normal and CRC tissue samples were collected from 122 patients with cancers across all stages and locations throughout the colon and rectum. These samples were stained for VCAN, αDPEAAE (neoepitope generated in cleaving VCAN to versikine), and CD8 and scored by a pathologist. Tumors were classified as VCAN proteolysis-predominant (VPP) if their staining for total VCAN staining intensity was < 1+ and staining for VCAN proteolysis (αDPEAAE antibody) was > 2. Conversely, tumors were classified as VCAN proteolysis-weak (VPW) if intact VCAN staining intensity was > 1+ or αDPEAAE intensity was < 2+. IHC for mismatch repair (MMR) proteins was also performed. Results: Overall increased VCAN staining was observed in cancer versus (vs) normal tissue. VPP tumors had a 10 fold greater infiltration of CD8+ T-cells vs VPW cancers (p < 0.001). The correlation between VCAN proteolysis and CD8+ T-cell infiltration was maintained in both cancers with proficient (p) MMR and deficient (d) MMR. In both pMMR and dMMR, the VPP tumors had the greatest degree of CD8+ T-cell infiltration (Wilcoxon rank sum tests: pMMR p = 0.006; dMMR p = 0.03). Among the VPP tumors there was a greater degree of CD8+ T cell infiltration in the dMMR cancers vs pMMR cancers (35 versus 14.8 TILs per high power filed, p = 0.04). Nuclear CTNNB1, a marker for activation of WNT signaling, negatively correlated with CD8+ T cell infiltration( p = 0.014). In addition, VCAN accumulation correlated with the presence of nuclear CTNNB1 (p < 0.001) Conclusions: This is the first description indicating that VCAN proteolysis may shape CRC immune contexture and provide a rationale for testing VCAN proteolysis as a predictive and/or prognostic immune biomarker.

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