1. Supplementary Table 1. Demographic and clinical characteristics of the analyzed patients

2. Supplementary Table 2. Antibodies and conditions used for the IHC studies.

3. Supplementary Table 3. List of immune-related genes analyzed by Low Density Array

4. Supplementary Figure S1. Gating and data analysis strategy.

5. PBL
RIL
TIL
CD4+ T cells
CD8+ T cells
Supplementary Figure S2. CD4+ and CD8+ T-cell differentiation in ccRCC TIL, and autologous PBL and RIL
Supplementary Figure 1

6. Supplementary Figure S3
Supplementary Figure S3. Gap statistics according to the possible number of clusters of TIL phenotype. Optimal cut-off according to firstSEmax method (R package: cluster) is displayed (dotted line).

7. Supplementary Figure S4. PCA analysis including RIL and TIL phenotype
Supplementary Figure S4. PCA analysis including RIL and TIL phenotype. TIL clusters are displayed.

8. Supplementary Figure S5. Tumor size according to TIL clusters.

9. CD40L CD69 CTLA-4 Naïve CM EM GITR ICOS Lag-3 PD-1 Tim-3 CD38 EMRA
C1 C2 C3
C1 C2 C3
C1 C2 C3
C1 C2 C3
Supplementary Figure S6. Percentages of CD4+TIL expressing AM and InR according to tumor clusters. C1, Cluster1; C2, Cluster2; C3, Cluster3.

10. CD38 CD69 GITR ICOS Naïve CM EM EMRA Lag-3 PD-1 Tim-3 C1 C2 C3
Supplementary Figure S7. Percentages of CD8+TIL expressing AM and InR according to tumor clusters. C1, Cluster1; C2, Cluster2; C3, Cluster3.

11. Supplementary Figure S8
Supplementary Figure S8. Clonality Index and frequency of top 15 clonotypes in CD8+PD-1+ TIL according to tumor clusters. C1, Cluster1; C2, Cluster2; C3, Cluster3.

12. ** *
P value
C1vs.C3
C2vs.C3
C1vs.C2
***
Supplementary Figure S9. Corrected P values for the differential gene expression between TIL clusters. Only significant P values are displayed. *P<0.05, **P < 0.01, ***P < C1, Cluster1; C2, Cluster2; C3, Cluster3.

13. Supplementary Figure S10
Supplementary Figure S10. Correlation matrix including TLS-related genes and immune cells densities in Immune-activated and Immune-regulated tumors.

14. CD40L CD69 CTLA-4 Naïve CM EM GITR ICOS Lag-3 PD-1 Tim-3 CD38 EMRA
ccRCC
ccRCC
ccRCC
ccRCC
ccRCC
ccRCC
ccRCC
ccRCC
ccRCC
ccRCC
ccRCC
ccRCC
ccRCC
Supplementary Figure S11. Percentages of CD4+PBL expressing differentiation markers, AM and InR in healthy controls (HC) and ccRCC-bearing patients.

15. CD38 CD69 GITR ICOS Naïve CM EM EMRA Lag-3 PD-1 Tim-3
ccRCC
ccRCC
ccRCC
ccRCC
ccRCC
ccRCC
ccRCC
ccRCC
ccRCC
ccRCC
ccRCC
Supplementary Figure S12. Percentages of CD8+PBL expressing differentiation markers, AM and InR in HC and ccRCC-bearing patients.

16. CD40L CD69 CTLA-4 Naïve CM EM GITR ICOS Lag-3 PD-1 Tim-3 CD38 EMRA
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
Supplementary Figure S13. Percentages of CD4+PBL expressing differentiation markers, AM and InR according to PBL Clusters.

17. CD38 CD69 GITR ICOS Naïve CM EM EMRA Lag-3 PD-1 Tim-3
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
PBL-A
PBL-B
Supplementary Figure S14. Percentages of CD8+PBL expressing differentiation markers, AM and InR according to PBL Clusters.