Analysis of the Tumor Immune Microenvironment (TIME) in Clear Cell Renal Cell Carcinoma (ccRCC) Reveals an M0 Macrophage-Enriched Subtype: An Exploration of Prognostic and Biological Characteristics of This Immune Phenotype
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Discovery Dataset
2.2. Clustering Based on Immune Cell Subpopulations
2.3. Survival Analysis by Clusters
2.4. Validation Dataset
2.5. Tumor Immune Characterization Using TIDE
2.6. Gene Set Enrichment Analysis (GSEA)
2.7. Multivariable Cox Hazards Analyses
3. Results
3.1. Cohort Description
3.2. Hierarchical Clustering Based on the Immune Cell Subsets Identified Macrophage-Enriched Clusters
3.3. M0 Macrophage Enrichment Is Associated with Shorter PFS in Two Separate Cohorts
3.4. M0 Macrophage Enrichment Is Also Associated with Other Pro-Tumorigenic TME Characteristics
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Cluster 1 (n = 77) | Cluster 2 (n = 116) | Cluster 3 (n = 94) | Cluster 4 (n = 25) | Cluster 5 (n = 70) | |
---|---|---|---|---|---|
Median Age (years) | 60.9 | 61.8 | 59.4 | 62.4 | 60.2 |
Gender (M/F, %) | 62/38 | 59/41 | 72/28 | 72/28 | 61/39 |
Race (W/B/A/NA, %) | 96/4/0/0 | 95/3/1/2 | 93/3/2/2 | 96/0/4/0 | 96/1/3/0 |
Laterality (R/L, %) | 61/39 | 53/47 | 53/47 | 60/40 | 46/54 |
Mutation Count (Min, Median, Max) | 1, 48, 553 | 1, 48, 708 | 1, 48, 409 | 1, 48, 89 | 1, 48, 93 |
Fraction Genome Altered (Mean %) | 15.9 | 13.3 | 16.1 | 23.4 | 15.9 |
Lab Parameters (↑/↓/WNL/NA %) | |||||
Serum Calcium | 3/44/23/30 | 1/41/27/32 | 0/49/17/34 | 0/60/16/24 | 1/43/26/30 |
Hemoglobin | 1/52/32/14 | 2/46/39/14 | 1/45/33/21 | 0/56/36/8 | 0/56/39/6 |
Platelet Count | 5/10/68/17 | 8/12/66/15 | 3/6/69/21 | 0/20/68/12 | 6/9/77/9 |
White Blood Cell Count | 34/0/48/0 | 38/3/44/16 | 40/1/36/22 | 32/4/52/12 | 37/1/54/8 |
Lymph Nodes + (%) | 0 | 8 | 16 | 10 | 23 |
Grade (%) | |||||
G1 | 5 | 3 | 0 | 4 | 1 |
G2 | 57 | 46 | 54 | 32 | 37 |
G3 | 25 | 41 | 39 | 52 | 46 |
G4 | 13 | 9 | 5 | 12 | 16 |
TNM Stage Group (%) | |||||
I | 60 | 53 | 68 | 40 | 49 |
II | 12 | 11 | 11 | 12 | 16 |
III | 27 | 35 | 19 | 48 | 34 |
IV | 1 | 0 | 1 | 0 | 1 |
Pathologic T Stage (%) | |||||
T1, T1a, T1b | 6, 26, 27 | 4, 32, 18 | 7, 38, 22 | 0, 20, 24 | 0, 20, 29 |
T2, T2a, T2b | 10, 1, 0 | 7, 3, 1 | 11, 0, 0 | 12, 0, 0 | 14, 1, 1 |
T3, T3a, T3b, T3c | 0, 17, 10, 0 | 1, 24, 8, 2 | 1, 17, 2, 0 | 0, 16, 28, 0 | 0, 21, 11, 0 |
T4 | 1 | 0 | 1 | 0 | 1 |
Mutations (% WT, MUT, NA) | |||||
TP53 | 90/1/9 | 90/4/6 | 87/2/11 | 88/0/12 | 90/0/10 |
VHL | 44/48/9 | 41/53/6 | 35/54/11 | 52/36/12 | 44/45/10 |
PBRM1 | 56/35/9 | 62/32/6 | 59/31/11 | 52/36/12 | 74.16.10 |
SETD2 | 75/16/9 | 87/7/6 | 82/7/11 | 76/12/12 | 84/6/10 |
TCEB1 | 91/0/9 | 93/1/6 | 88/1/11 | 88/0/12 | 89/1/10 |
Predicted ICB Response (%) | 27 | 23 | 20 | 4 | 34 |
Cluster 1 (n = 9) | Cluster 2 (n = 9) | Cluster 3 (n = 25) | Cluster 4 (n = 17) | Cluster 5 (n = 28) | Cluster 6 (n = 11) | |
---|---|---|---|---|---|---|
Median Age (years) | 61.1 | 64.1 | 58.6 | 64.2 | 57.6 | 63.7 |
Gender (M/F, %) | 78/22 | 78/22 | 84/16 | 65/35 | 64/36 | 73/27 |
Race (W/B/A/NA, %) | 22/0/0/78 | 67/0/0/33 | 48/0/0/52 | 47/0/0/53 | 54/4/4 38 | 64/0/0/36 |
BMI (Mean) | 25.3 | 28.3 | 33.2 | 32.4 | 31.9 | 30.8 |
Tumor Site (LP, M, UP, OTH, %) | 11, 22, 33, 33 | 0, 11, 33, 56 | 12, 20, 32, 36 | 6, 35, 24, 35 | 14, 29, 29, 29 | 36, 18, 27, 18 |
Tumor Size (Mean, cm) | 6.04 | 8.56 | 6.33 | 6.77 | 5.64 | 5.79 |
Grade (%) | ||||||
G1 | 0 | 0 | 0 | 24 | 7 | 0 |
G2 | 89 | 22 | 52 | 35 | 57 | 45 |
G3 | 11 | 44 | 44 | 41 | 29 | 55 |
G4 | 0 | 33 | 4 | 0 | 7 | 0 |
Pathologic Stage (%) | ||||||
I | 44 | 33 | 40 | 53 | 50 | 55 |
II | 11 | 11 | 16 | 18 | 7 | 18 |
III | 22 | 22 | 40 | 24 | 32 | 27 |
IV | 11 | 33 | 4 | 6 | 11 | 0 |
Pathologic T Stage (%) | ||||||
T1, T1a, T1b | 0, 22, 22 | 0, 11, 22 | 0, 20, 20 | 0, 18, 35 | 0, 39, 14 | 0, 36, 27 |
T2, T2a, T2b | 0, 11, 0 | 0, 11, 11 | 0, 8, 8 | 0, 18, 0, 0 | 0, 4, 4 | 0, 9, 9, |
T3, T3a, T3b, T3c | 11, 11, 0, 0 | 11, 11, 22, 0 | 4, 36, 4, 0 | 0, 18, 6, 0 | 4, 36, 0, 0 | 0, 18, 0 |
T4 | 11 | 0 | 0 | 6 | 0 | 0 |
Lab Parameters (↑/↓/WNL/NA %) | ||||||
Serum Calcium | 0/0/11/89 | 0/0/56/44 | 0/8/16/76 | 0/12/18/70 | 4/4/18/75 | 0/18/0/82 |
Hemoglobin (HgB) | 0/11/56/33 | 0/22/56/22 | 0/28/36/36 | 0/39/22/35 | 0/32/32/36 | 9/27/27/36 |
Platelets (PLT) | 0/0/67/33 | 0/0/78/22 | 0/0/59/41 | 0/0/61/39 | ||
White Blood Cells (WBC) | 0/0/67/33 | 0/0/78/22 | 0/0/64/36 | 6/0/59/35 | 11/4/50/35 | 0/9/55/36 |
Laterality (L/R, %) | 78/22 | 56/44 | 40/60 | 29/71 | 46/54 | 73/27 |
Margins Involved (%) | 22 | 22 | 4 | 0 | 0 | 9 |
Residual Tumor | ||||||
R0 | 44 | 67 | 52 | 59 | 43 | 36 |
R1 | 0 | 0 | 4 | 0 | 0 | 0 |
R2 | 0 | 0 | 0 | 0 | 0 | 0 |
Rx | 56 | 33 | 44 | 41 | 57 | 64 |
Pack Years (Mean) | 22.9 | 18.3 | 34 | 36.5 | 26.3 | 14.7 |
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Farha, M.; Nallandhighal, S.; Vince, R.; Cotta, B.; Stangl-Kremser, J.; Triner, D.; Morgan, T.M.; Palapattu, G.S.; Cieslik, M.; Vaishampayan, U.; et al. Analysis of the Tumor Immune Microenvironment (TIME) in Clear Cell Renal Cell Carcinoma (ccRCC) Reveals an M0 Macrophage-Enriched Subtype: An Exploration of Prognostic and Biological Characteristics of This Immune Phenotype. Cancers 2023, 15, 5530. https://doi.org/10.3390/cancers15235530
Farha M, Nallandhighal S, Vince R, Cotta B, Stangl-Kremser J, Triner D, Morgan TM, Palapattu GS, Cieslik M, Vaishampayan U, et al. Analysis of the Tumor Immune Microenvironment (TIME) in Clear Cell Renal Cell Carcinoma (ccRCC) Reveals an M0 Macrophage-Enriched Subtype: An Exploration of Prognostic and Biological Characteristics of This Immune Phenotype. Cancers. 2023; 15(23):5530. https://doi.org/10.3390/cancers15235530
Chicago/Turabian StyleFarha, Mark, Srinivas Nallandhighal, Randy Vince, Brittney Cotta, Judith Stangl-Kremser, Daniel Triner, Todd M. Morgan, Ganesh S. Palapattu, Marcin Cieslik, Ulka Vaishampayan, and et al. 2023. "Analysis of the Tumor Immune Microenvironment (TIME) in Clear Cell Renal Cell Carcinoma (ccRCC) Reveals an M0 Macrophage-Enriched Subtype: An Exploration of Prognostic and Biological Characteristics of This Immune Phenotype" Cancers 15, no. 23: 5530. https://doi.org/10.3390/cancers15235530