Checkpoint molecule PD-1-assisted CD8⁺ T lymphocyte count in tumor microenvironment predicts overall survival of patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors

Abstract

PurposeThe aim of this study was to determine whether CD8+ T lymphocyte and its checkpoint-associated module programmed cell death protein 1 (PD-1)/main ligand of PD-1 (PD-L1) pathway impact overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitors (TKIs).Materials and methodsA total of 231 mRCC patients, from 2007 to 2017, treated with sunitinib or sorafenib in Zhongshan Hospital, Fudan University were included in the study analyses. CD8, PD-1, and PD-L1 was assessed by immunohistochemistry on continuous paraffin-embedded slides. Kaplan–Meier method and COX regression model were applied in the survival analyses.ResultsBaseline characteristics were comparable between the training (n=118) and validation (n=113) sets. Patients with high CD8+ T lymphocytes infiltration and low PD-1 expression had longer survival in both sets (P=0.0106 and P=0.0047 in training set, P=0.0291 and P=0.0011 in validation set, respectively). However, survival stratified by PD-L1 was only insignificant or marginally significant. Multivariable analyses verified that CD8+ T lymphocytes, together with PD-1, but not tumor infiltrating mononuclear cells or tumor cells PD-L1, were independent prognostic factors (training set [HR 3.202, 95% CI 1.433–7.153, P=0.011] and validation set [HR 4.012, 95% CI 2.354–6.838, P<0.001]). Subsequent analysis revealed that the PD-1 high/CD8 low group had shorter survival (16 months) than PD-1 low/CD8 high group (51 months, P<0.0001). Combining the International Metastatic Renal Cancer Database Consortium system with the PD-1/CD8 model exhibited much better accuracy for the prediction of OS.ConclusionOur findings suggest that abundant CD8+ T cells are significantly associated with longer OS in mRCC patients treated with TKIs. The most influential checkpoint-associated molecule, PD-1, assisted CD8+ T cell-stratified patients and could be used as a better predictive and prognostic factor for the mRCC patients.

Immune Cell Infiltration and Identifying Genes of Prognostic Value in the Papillary Renal Cell Carcinoma Microenvironment by Bioinformatics Analysis

“…It should be noted that multiple immune escape mechanisms exist in tumors to inhibit CD8+ T cell attacks. A high level of CD4+/CD8+ T cells is linked with an extended prognosis in various tumors [ 31 – 34 ], but we failed to establish this correlation in the present study, thereby implying that macrophages might play more important roles in PRCC rather than CD4+/CD8+ cells [ 35 ].…”

Tumour immune microenvironment in primary and metastatic papillary renal cell carcinoma

“…Looking at patients with metastatic RCC treated with tyrosine kinase inhibitors, Yao et al . found a better overall survival in patients with a high number of CD8 + T cells . In contrast, Hotta et al .…”

Immune infiltration in renal cell carcinoma

“…Infiltrating CD4+ T cells can regulate RCC cell proliferation by modulating the TGFβ1/YBX1/HIF2α signal . A high level of activated CD8+ T cells is associated with prolonged prognosis in many cancers, including RCC . However, the tumor microenvironment can also inhibit T cell responses, causing tumors to lose their immunogenicity.…”

“…9 A high level of activated CD8+ T cells is associated with prolonged prognosis in many cancers, including RCC. 10,11 However, the tumor microenvironment can also inhibit T cell responses, causing tumors to lose their immunogenicity. This involve regulatory T cells (Tregs), that secrete immunosuppressive cytokines, leading to T cell dysfunction.…”