CD8 lymphocytes in tumors and nonsynonymous mutational load correlate with prognosis of bladder cancer patients treated with immune checkpoint inhibitors.

Anti-programed cell death 1 checkpoint inhibitors have recently demonstrated effectiveness against metastatic cancers including urothelial carcinoma. To identify biomarkers/factors that correlate with the clinical response in advanced bladder cancer patients who received immune checkpoint inhibitor treatment. We investigated tumors from 18 bladder cancer patients who had received anti-programed cell death 1 (pembrolizumab) or anti-programmed death-ligand 1 therapy (atezolizumab or durvalumab) and performed exome analysis, T-cell receptor sequencing of the tumor-infiltrating lymphocytes (TILs), and immunohistochemical analysis of CD8 and programmed death-ligand 1 in cancer tissues. Immunohistochemical analysis of bladder cancer tissues demonstrated that a higher number of CD8 T-cell infiltration into cancer tissues was significantly associated with longer cancer-specific survival of the patients (P = .0012). T-cell receptor beta sequencing of TILs using genomic DNAs extracted from the tissues of 15 cases revealed that patients with higher clonal expansion of TILs had some tendency of longer cancer-specific survival (P = .055), than those with lower clonal expansion. We performed whole exome sequencing of 14 cases and found that patients carrying higher numbers of somatic mutations received greater benefit from immunotherapy (P = .034) and one patient who had high microsatellite instability has survived for 1034 days. CD8 infiltration in tumors and nonsynonymous mutation load might be useful predictive markers for immune checkpoint inhibitors for bladder cancer patients.

Deng B ，Park JH ，Ren L ，Yew PY ，Kiyotani K ，Antic T ，O'Connor K ，O'Donnell PH ，Nakamura Y ... -  《Cancer Reports》

TOX-expressing terminally exhausted tumor-infiltrating CD8(+) T cells are reinvigorated by co-blockade of PD-1 and TIGIT in bladder cancer.

Exhausted T cells in the tumor microenvironment are major targets of immunotherapies. However, the exhaustion status of CD8+ tumor-infiltrating lymphocytes (TILs) in bladder cancer has not been comprehensively evaluated. Herein, we examined distinct exhaustion status of CD8+ TILs based on the level of programmed cell death-1 (PD-1) and thymocyte selection-associated high mobility group box protein (TOX) expression in urothelial bladder cancer. We also evaluated the reinvigoration of exhausted CD8+ TILs upon ex vivo treatment with inhibitory checkpoint blockers. TOX-expressing PD-1highCD8+ TILs had the highest expression of immune checkpoint receptors (ICRs), the most terminally exhausted features, and the highest tumor antigen reactivity among PD-1+CD8+ TILs. Bladder cancer patients with a high percentage of PD-1highTOX+CD8+ TILs had more progressed T-cell exhaustion features and higher programmed death-ligand 1 expression in tumor tissues. TIGIT was the most frequent co-expressed ICR on PD-1+CD8+ TILs, and TIGIT blockade enhanced the PD-1 blockade-mediated cytokine production by CD8+ TILs from bladder cancer patients. Our findings provide an improved understanding of the heterogeneous exhaustion status of CD8+ TILs and additional immunotherapy strategies to improve outcomes of bladder cancer patients.

Han HS ，Jeong S ，Kim H ，Kim HD ，Kim AR ，Kwon M ，Park SH ，Woo CG ，Kim HK ，Lee KH ，Seo SP ，Kang HW ，Kim WT ，Kim WJ ，Yun SJ ，Shin EC ... -  《-》

RB1 and TP53 co-mutations correlate strongly with genomic biomarkers of response to immunity checkpoint inhibitors in urothelial bladder cancer.

Manzano RG ，Catalan-Latorre A ，Brugarolas A 《BMC CANCER》

Identification of a novel immune microenvironment signature predicting survival and therapeutic options for bladder cancer.

Yan Y ，Huang Z ，Cai J ，Tang P ，Zhang F ，Tan M ，Shen B ... -  《Aging-US》

Genomic stratification based on microenvironment immune types and PD-L1 for tailoring therapeutic strategies in bladder cancer.

Lyu X ，Wang P ，Qiao Q ，Jiang Y ... -  《BMC CANCER》