Tumor-Infiltrating and Peripheral Blood T-cell Immunophenotypes Predict Early Relapse in Localized Clear Cell Renal Cell Carcinoma

Abstract

The efficacy of PD-1 checkpoint blockade as adjuvant therapy in localized clear cell renal cell carcinoma (ccRCC) is currently unknown. The identification of tumor microenvironment (TME) prognostic biomarkers in this setting may help define which patients could benefit from checkpoint blockade and uncover new therapeutic targets. We performed multiparametric flow cytometric immunophenotypic analysis of T cells isolated from tumor tissue [tumor-infiltrating lymphocytes (TIL)], adjacent non-malignant renal tissue [renal-infiltrating lymphocytes (RIL)], and peripheral blood lymphocytes (PBL), in a cohort of patients ( = 40) with localized ccRCC. Immunophenotypic data were integrated with prognostic and histopathologic variables, T-cell receptor (TCR) repertoire analysis of sorted CD8PD-1 TILs, tumor mRNA expression, and digital quantitative immunohistochemistry. On the basis of TIL phenotypic characterization, we identified three dominant immune profiles in localized ccRCC: (i) immune-regulated, characterized by polyclonal/poorly cytotoxic CD8PD-1Tim-3Lag-3 TILs and CD4ICOS cells with a Treg phenotype (CD25CD127Foxp3/HeliosGITR), that developed in inflamed tumors with prominent infiltrations by dysfunctional dendritic cells and high PD-L1 expression; (ii) immune-activated, enriched in oligoclonal/cytotoxic CD8PD-1Tim-3 TILs, that represented 22% of the tumors; and (iii) immune-silent, enriched in TILs exhibiting RIL-like phenotype, that represented 56% of patients in the cohort. Only immune-regulated tumors displayed aggressive histologic features, high risk of disease progression in the year following nephrectomy, and a CD8PD-1Tim-3 and CD4ICOS PBL phenotypic signature. In localized ccRCC, the infiltration with CD8PD-1Tim-3Lag-3 exhausted TILs and ICOS Treg identifies the patients with deleterious prognosis who could benefit from adjuvant therapy with TME-modulating agents and checkpoint blockade. This work also provides PBL phenotypic markers that could allow their identification. .

Programmed death ligand‐1 is associated with tumor infiltrating lymphocytes and poorer survival in urothelial cell carcinoma of the bladder

“…Moreover, a high ratio of CD68 + macrophages/CD3 + TIL was identified as a bad prognosis group among muscle‐invasive bladder cancer . Similarly, associations of PD‐L1 expression and high stromal CD8 + TIL density with poor outcome have been reported in renal cell carcinoma …”

Implications of the tumor immune microenvironment for staging and therapeutics

“…99,100 In fact, renal cell carcinoma is one of the few cancer types where increased densities of CD8+, CD4+, and PD-1+ tumorinfiltrating T cells correlate with poor clinical outcomes. 101–103 The second type of microenvironment is more consistent with what is typically seen in other tumor types, namely, the CD8+ infiltrate is activated and represents an ongoing antitumor response that is associated with an improved prognosis. This phenotype has been characterized by using CD8 and Ki-67 double immunohistochemistry staining or the presence of an IFN- γ /Th1-type gene signature.…”

“…104 PD-L1 and PD-L2 expression has also been reported in renal cell carcinoma. 73,103,105,106 However, the relationship between the two tumor immune microenvironments and the presence and pattern (adaptive vs constitutive) of PD-L1 and PD-L2 expression has yet to be thoroughly explored.…”

Paraneoplastic vasculitis in patients with metastatic renal cell carcinoma

“…The higher prevalence of PV in patients with metastatic renal cell carcinoma could be explained by the immunogenicity of this type of tumour. It is well known that growth of renal cell carcinoma is associated with impaired autoimmune and antitumor immune response, which involves T cells, natural killer cells, dendritic cells, and macrophages . Cross‐reactivity between the antigens of the tumour and the endothelial cell is believed to be one of the essential mechanisms of an autoimmune process; fibrin deposits are found in the vascular wall in this case.…”