Cancer immunotherapy comes of age

Mellman, Ira; Coukos, George; Dranoff, Glenn

doi:10.1038/nature10673

Cited by 3,356 publications

(2,828 citation statements)

References 97 publications

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“…Immunotherapy has emerged as a promising approach for cancer treatment, 9 , 10 and checkpoint inhibitors, targeting PD-1 or PD-L1, have demonstrated objective response in several types of cancer, including melanoma, non-small cell lung cancer, and renal cell carcinoma, among others. 11 In CRC, the clinical benefit of PD-1 or PD-L1 blockade remains uncertain, however, a few studies report a positive effect of anti-PD-1 antibodies in patients with microsatellite instability (MSI) high tumours 12 , 13 and anti-PD-1 therapies were recently approved by the U.S Food and Drug Administration for treatment of any type of advanced MSI-high cancer.…”

Section: Introductionmentioning

confidence: 99%

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

et al. 2018

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Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 has been demonstrated to confer a prognostic value in colorectal cancer (CRC), but no studies have investigated whether this association differs according to tumour location. In this study, immunohistochemical expression of PD-1 and PD-L1 was analysed in tissue microarrays with primary tumours from 557 incident CRC cases from a prospective population-based cohort. Univariable and multivariable Cox regression analyses, adjusted for age, sex, TNM stage, differentiation grade and vascular invasion, were applied to determine the impact of biomarker expression on 5-year overall survival (OS), in the entire cohort and in subgroup analysis of right colon, left colon, and rectum. High PD-L1 expression on tumour-infiltrating immune cells was an independent factor of a prolonged OS in the entire cohort (hazard ratio [HR] = 0.49; 95% confidence interval [CI] CI 0.35 – 0.68), and in tumours of the right colon (HR = 0.43; 95% CI 0.25 – 0.74) and the left colon (HR = 0.28; 95% CI 0.13 – 0.61), but not in rectal cancer. Tumour-specific PD-L1-expression was not prognostic, neither in the full cohort nor according to tumour location. High immune cell-specific PD-1 expression was associated with a prolonged OS in the entire cohort and in tumours of the right colon, but not in the left colon or rectum, and only in univariable analysis. In conclusion, these results demonstrate that immune cell-specific PD-L1 and PD-1 expression is prognostic in a site-dependent manner, whereas tumour-specific PD-L1-expression is not prognostic in CRC.

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Section: Introductionmentioning

confidence: 99%

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

et al. 2018

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“…5–7 Anti-PD-L1 and anti-PD-1 antibody immunotherapies block the immune-suppressive actions of PD-L1/PD-1 to mediate durable responses and have become standard of care for multiple cancer types. 8–14 However, these antitumor immunotherapies are only effective for a subset of cancer patients and are not usually curative. In particular, clinical efficacy of anti-PD-1 antibodies in other solid tumors such as triple-negative breast cancer is modest.…”

Section: Introductionmentioning

confidence: 99%

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Sun

Gupta

et al. 2018

OncoImmunology

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Programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) modulate antitumor immunity and are major targets of checkpoint blockade immunotherapy. However, clinical trials of anti-PD-L1 and anti-PD-1 antibodies in breast cancer demonstrate only modest efficacy. Furthermore, specific PD-L1 contributions in various tissue and cell compartments to antitumor immunity remain incompletely elucidated. Here we show that PD-L1 expression is markedly elevated in mature adipocytes versus preadipocytes. Adipocyte PD-L1 prevents anti-PD-L1 antibody from activating important antitumor functions of CD8+ T cells in vitro. Adipocyte PD-L1 ablation obliterates, whereas forced preadipocyte PD-L1 expression confers, these inhibitory effects. Pharmacologic inhibition of adipogenesis selectively reduces PD-L1 expression in mouse adipose tissue and enhances the antitumor efficacy of anti-PD-L1 or anti-PD-1 antibodies in syngeneic mammary tumor models. Our findings provide a previously unappreciated approach to bolster anticancer immunotherapy efficacy and suggest a mechanism for the role of adipose tissue in breast cancer progression.

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“…Early results show that only a fraction (about 15%) of treated patients clinically respond to immunotherapy. 4 , 5 However, once an anti-tumor response is activated, this correlates with better survival. 6-9 An important part of the battle between tumor cells and the immune system is fought within, but not confined to, the tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

The blood mMDSC to DC ratio is a sensitive and easy to assess independent predictive factor for epithelial ovarian cancer survival

et al. 2018

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Epithelial ovarian cancer (EOC) may cause abnormal blood levels of leukocytes. This paraneoplastic manifestation is associated with a worse response to therapy and shorter survival. To understand the complexity and nature of these leukocytes, we dissected the different populations of myeloid cells and analyzed their relation to clinical outcome. Therefore, baseline blood samples of 36 EOC patients treated either with carboplatin/doxorubucin or with gemcitabine were analyzed for different subsets of monocytes/macrophages, myeloid derived suppressor cells (MDSC) and dendritic cells (DC) using multiparameter flow cytometry as well as functional assays for myeloid cell mediated suppression of antigen-specific T cell reactivity. Healthy donor blood served as control. EOC patients displayed an increase in monocytes/macrophages, monocytic MDSC (mMDSC) and CD33-CD11b+CD14-CD15- double-negative MDSC (CD33- dnMDSC) and a decrease in the frequency of DC, across all EOC subtypes. A low frequency of DC and high frequencies of monocytes/macrophages and mMDSC, but not CD33- dnMDSC, were associated with poor overall survival. Patient's monocytes/macrophages and mMDSC, but not CD33- dnMDSC, were shown to suppress T cell reactivity in vitro. The mMDSC and DC frequencies were not altered upon treatment. Importantly, the mMDSC to DC ratio was the strongest independent, highly sensitive and specific, predictive factor for survival. This was irrespective of the type of chemotherapy or disease stage and outperformed classical parameters as WHO status or time from last chemotherapy. Thus, the baseline blood mMDSC to DC ratio is a robust, independent and easy to analyze predictive factor for EOC survival, and may assist patient selection for immunotherapy.

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Cancer immunotherapy comes of age

Cited by 3,356 publications

References 97 publications

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

The blood mMDSC to DC ratio is a sensitive and easy to assess independent predictive factor for epithelial ovarian cancer survival

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