A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization

Sanmamed, Miguel F.; Chen, Lieping

doi:10.1016/j.cell.2018.09.035

Cited by 1,078 publications

(609 citation statements)

References 111 publications

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“…We also revealed the independent prognostic value of several important immune checkpoint modulators in KIRC and KIRP. Blocking immune checkpoints is currently the most promising strategy for cancer immunotherapy . Our results showed that CTLA4, LAG3 and TIGIT were associated with a worse prognosis in KIRC, and that LAG3 and PD‐L2 were associated with a poor outcome in KIRP.…”

Section: Discussionmentioning

confidence: 56%

Immune infiltration in renal cell carcinoma

et al. 2019

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Immune infiltration of tumors is closely associated with clinical outcome in renal cell carcinoma ( RCC ). Tumor‐infiltrating immune cells ( TIIC s) regulate cancer progression and are appealing therapeutic targets. The purpose of this study was to determine the composition of TIIC s in RCC and further reveal the independent prognostic values of TIIC s. CIBERSORT , an established algorithm, was applied to estimate the proportions of 22 immune cell types based on gene expression profiles of 891 tumors. Cox regression was used to evaluate the association of TIIC s and immune checkpoint modulators with overall survival ( OS ). We found that CD 8+ T cells were associated with prolonged OS (hazard ratio [ HR ] = 0.09, 95% confidence interval [ CI ].01‐.53; P = 0.03) in chromophobe carcinoma ( KICH ). A higher proportion of regulatory T cells was associated with a worse outcome ( HR = 1.59, 95% CI 1.23‐.06; P < 0.01) in renal clear cell carcinoma ( KIRC ). In renal papillary cell carcinoma ( KIRP ), M1 macrophages were associated with a favorable outcome ( HR = .43, 95% CI .25‐.72; P < 0.01), while M2 macrophages indicated a worse outcome ( HR = 2.55, 95% CI 1.45‐4.47; P < 0.01). Moreover, the immunomodulator molecules CTLA 4 and LAG 3 were associated with a poor prognosis in KIRC , and IDO 1 and PD ‐L2 were associated with a poor prognosis in KIRP . This study indicates TIIC s are important determinants of prognosis in RCC meanwhile reveals potential targets and biomarkers for immunotherapy development.

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Section: Discussionmentioning

confidence: 56%

Immune infiltration in renal cell carcinoma

et al. 2019

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“…Many suppressive mechanisms have been recognized, such as the functional impairment or deletion of tumor‐reactive T lymphocytes to suppress T cell function. The recent discovery and definition of the immune escape mechanism in carcinoma development suggested that the mechanism of immune escape leads to local rather than systemic immunosuppression . With the progressing study of the PD‐1‐mediated tumor escape mechanism and its successful application in the clinical treatment of tumors, the PD‐1/PD‐L1 pathway has been discovered to be a key adaptive immune escape mechanism of tumors.…”

Section: Discussionmentioning

confidence: 99%

CD137 ligand feedback upregulates PD‐L1 expression on lung cancer via T cell production of IFN‐γ

et al. 2019

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Background The expression of PD‐L1 and its regulation in tumors remains unclear. The importance of IFN‐γ in upregulating the PD‐L1 expression in various tumors, and the effects of other essential cytokines in the tumor microenvironment (TME), need to be further elucidated. Methods Constitutive expression of PD‐L1 and CD137L in all 13 lung cancer cell lines were tested by flow cytometry. CD137L mRNA of lung cancer cell lines was detected by RT‐PCR. PD‐L1 expression rates following stimulation with these cytokines (IFN‐γ, TNFα and IL2) were measured. After coculture of cells expressing CD137L (lung cancer cells or 293FT cells transfected with CD137L plasmid) with T cells, the PDL1 expression of lung cancer cells and IFN‐γ in supernatant was detected. Results Our data revealed that adenocarcinoma and squamous cell carcinoma cells had the highest positive expression rate. IFN‐γ was the core‐inducing factor for enhancing the PD‐L1 expression. CD137L was also widely expressed in the lung cancer cell lines at the mRNA level, whereas its expression was generally low at the protein level. However, the low expression of CD137L protein was still enough to induce T cells to produce IFN‐γ, which subsequently increased the PD‐L1 expression by lung cancer cells. The CD137 signal induces IFN‐γ secretion by T cells, which stimulates high‐level of PD‐L1 expression in cancer cells; this negative immune regulation may represent a mechanism of immune escape regulation. Conclusions CD137L mRNA was widely expressed in lung cancer cell lines whereas levels of protein expression were generally low. The low level of CD137L protein was still enough to induce T cells to produce IFN‐γ that subsequently increased PD‐L1 expression. The CD137L‐induced negative immune regulation may represent a mechanism of immune escape.

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“…PD‐L1 is an immune checkpoint protein expressed in some tumor cells and tumor‐infiltrating immune cells involved in adaptive immune resistance through escape from T‐cell surveillance . The programmed cell death protein 1 (PD‐1) is an inhibitory receptor originally identified in T lymphocytes that, on interaction with PD‐L1, delivers inhibitory signals that downregulate T‐cell function.…”

Section: Introductionmentioning

confidence: 99%

Programmed death–ligand 1 expression on direct Pap‐stained cytology smears from non–small cell lung cancer: Comparison with cell blocks and surgical resection specimens

Lozano

Abengozar-Muela

Echeveste

et al. 2019

Cancer Cytopathology

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Background Programmed death–ligand 1 (PD‐L1) expression, as assessed by immunohistochemistry (IHC), is used to select patients with non–small cell lung cancer (NSCLC) for anti‐programmed cell death protein 1 (PD‐1)/PD‐L1 therapy. The current study evaluated the feasibility and efficacy of PD‐L1 immunostaining and quantitation on direct Papanicolaou‐stained cytological smears compared with formalin‐fixed paraffin‐embedded samples (cytological cell blocks and surgical resection specimens) in NSCLC cases using 2 commercially available assays: the PD‐L1 IHC 22C3 pharmDx assay (Agilent Technologies/Dako, Carpinteria, CA, USA) and the Ventana SP263 Assay (Ventana Medical Systems Inc, Tucson, Arizona). Methods PD‐L1 immunostaining using either both or one of the assays was tested in 117 sets of paired samples obtained from 62 NSCLC cases. The tumor proportion score was reported in every case following the recommendations of the International Association for the Study of Lung Cancer (IASLC). Results In 57 sets of samples, both PD‐L1 assays were used. Due to the availability of samples, only 1 assay was performed in 3 sets of samples and in 2 cases, only cytology smears were used and tested for both assays. A total of 113 sets of paired samples finally were evaluated; 4 cases could not be studied due to intense nonspecific background staining. A significant concordance between the 2 assays on cytological smears was found. Concordance between paired cytological smears and formalin‐fixed paraffin‐embedded samples was observed in 97.3% of the cases. Conclusions The quantification of PD‐L1 expression on direct Papanicolaou‐stained cytology smears is feasible and reliable for both PD‐L1 assays.

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A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization

Cited by 1,078 publications

References 111 publications

Immune infiltration in renal cell carcinoma

Immune infiltration in renal cell carcinoma

CD137 ligand feedback upregulates PD‐L1 expression on lung cancer via T cell production of IFN‐γ

Programmed death–ligand 1 expression on direct Pap‐stained cytology smears from non–small cell lung cancer: Comparison with cell blocks and surgical resection specimens

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