The efficacy of PD-1/PD-L1 blockade in cold cancers and future perspectives

Majidpoor, Jamal; Mortezaee, Keywan

doi:10.1016/j.clim.2021.108707

Cited by 157 publications

(113 citation statements)

References 99 publications

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“…PD-L1 positivity of tumor cells has been shown to be a good indicator of response to ICI therapy. In recent years, it has been recognized that high PD-L1 expression in dendritic cells, regulatory T cells, and macrophages can attenuate T cell activation and promote T cell exhaustion ( 61 ). The expression of PD-1 or PD-L1 in the TME is important for ICI therapy.…”

Section: Discussionmentioning

confidence: 99%

Tumor-Infiltrating PD-1hiCD8+-T-Cell Signature as an Effective Biomarker for Immune Checkpoint Inhibitor Therapy Response Across Multiple Cancers

et al. 2021

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BackgroundStratification of patients who could benefit from immune checkpoint inhibitor (ICI) therapy is of much importance. PD-1hiCD8+ T cells represent a newly identified and effective biomarker for ICI therapy response biomarker in lung cancer. Accurately quantifying these T cells using commonly available RNA sequencing (RNA-seq) data may extend their applications to more cancer types.MethodWe built a transcriptome signature of PD-1hiCD8+ T cells from bulk RNA-seq and single-cell RNA-seq (scRNA-seq) data of tumor-infiltrating immune cells. The signature was validated by flow cytometry and in independent datasets. The clinical applications of the signature were explored in non-small-cell lung cancer, melanoma, gastric cancer, urothelial cancer, and a mouse model of breast cancer samples treated with ICI, and systematically evaluated across 21 cancer types in The Cancer Genome Atlas (TCGA). Its associations with other biomarkers were also determined.ResultsSignature scores could be used to identify the PD-1hiCD8+ T subset and were correlated with the fraction of PD-1hiCD8+ T cells in tumor tissue (Pearson correlation, R=0.76, p=0.0004). Furthermore, in the scRNA-seq dataset, we confirmed the capability of PD-1hiCD8+ T cells to secrete CXCL13, as well as their interactions with other immune cells. In 581 clinical samples and 204 mouse models treated with ICIs, high signature scores were associated with increased survival, and the signature achieved area under the receiver operating characteristic curve scores of 0.755 (ranging from 0.61 to 0.91) in predicting therapy response. In TCGA pan-cancer datasets, our signature scores were consistently correlated with therapy response (R=0.78, p<0.0001) and partially explained the diverse response rates among different cancer types. Finally, our signature generally outperformed other mRNA-based predictors and showed improved predictive performance when used in combination with tumor mutational burden (TMB). The signature score is available in the R package “PD1highCD8Tscore” (https://github.com/Liulab/PD1highCD8Tscore).ConclusionThrough estimating the fraction of the PD-1hiCD8+ T cell, our signature could predict response to ICI therapy across multiple cancers and could serve as a complementary biomarker to TMB.

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Section: Discussionmentioning

confidence: 99%

Tumor-Infiltrating PD-1hiCD8+-T-Cell Signature as an Effective Biomarker for Immune Checkpoint Inhibitor Therapy Response Across Multiple Cancers

et al. 2021

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“…This indicates that tumors at advanced stages develop specific mutations and resistance in the genomic landscape (Davis et al, 2020). High tumor mutational burden (TMB) despite facilitating resistance to chemotherapy, can be a biomarker of higher response to the immune checkpoint inhibitor (ICI) therapy (Majidpoor & Mortezaee, 2021b) (Figure 1).…”

Section: Normalization Versus Abnormality In Health and Diseasementioning

confidence: 99%

“…ICI monotherapy has no effect on pancreatic ductal adenocarcinoma (PDAC). Thus, the functionality of infiltrated T cells is more important than the infiltration rate (Majidpoor & Mortezaee, 2021b; Mortezaee, 2021a). To explain, tumors like breast, ovary, prostate, pancreas, and colorectal cancer (CRC) are generally placed into the category of cold immunity.…”

Section: Cells and Signaling Of The Tme And The Characteristics Of An Abnormal Stromal Bed In A Tumormentioning

confidence: 99%

Normalization in tumor ecosystem: Opportunities and challenges

Mortezaee

2021

Cell Biology International

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Current research in cancer therapy aims to exploit efficient strategies to have long‐lasting effects on tumors and to reduce or even revoke the chance of recurrence. Within the tumor stroma, O2 and nutrients are abnormally distributed between various cells (preferentially for supplying cancer cells), the immune contexture is abnormally positioned (permissive essentially for cells exhibiting tumor‐promoting capacity), the fibroblast and fibrotic content is abnormally distributed (presence of both extracellular matrix [ECM] stiffening and ECM‐degrading factors both for tumor‐promoting purposes), and the tumor vasculature is abnormally orchestrated (for hindering drug delivery and increasing the chance of tumor metastasis). Resistance is actually an adaptive response to an imbalance in the tumor ecosystem; thus, the key consideration for effective cancer therapy is to bring back the normal status in this ecosystem so as to reach the desired durable outcome. Vascular normalization, metabolic modulation (glucose delivery in particular), balancing cellular dispersion, and balancing the pH rate and O2 delivery within the tumor microenvironment are suggested strategies to reverse abnormality within the tumor stroma.

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“…CD8+ cytotoxic T lymphocytes isolated from prostate cancer appear to have undergone clonal expansion in response to a certain antigen as they exhibit restricted T cell receptor Vβ gene usage 25 ; however, in some patients, near 90% of these prostate‐infiltrating CD8+ T cells are positive for programmed cell death protein 1 (PD‐1), 25 a cell surface immune‐suppressive checkpoint protein associated with self‐tolerance by suppressing T cell immune activity. These PD‐1 expressing cytotoxic T cells are likely incapable of mounting an effective immune response 25–28 . Cytotoxic T cell activity of killing tumor cells can also be weakened by the cancer cell production of decoy molecules against Fas and TRAIL‐induced death pathways (i.e., decoy receptor 3 [DcR3] and decoy receptor 4 [DcR4, aka TRAILR4]) 29 .…”

Section: Introductionmentioning

confidence: 99%

Immunotherapy in treatment of metastatic prostate cancer: An approach to circumvent immunosuppressive tumor microenvironment

Sun

2021

The Prostate

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Prostate cancer is the second most common cause of cancer‐related death in men in the United States and the fifth worldwide. Most prostate cancer arises as an androgen‐dependent tumor but eventually progresses into castration‐resistance prostate cancer, incurable by the current androgen deprivation therapy and chemotherapy. The development of immunotherapy in cancer treatment has brought an exciting era of antiprostate cancer therapy through antitumor immune responses. Prostate cancer is recognized as a poorly immunogenic tissue with immunological ignorance showing low levels of antigen‐presenting process and cytotoxic T‐cell activation, high levels of immune checkpoint molecules and immunosuppressive cytokines/chemokines, and recruitment of immunosuppressive cells. Immunotherapies for prostate cancer have been developed to activate the innate and adaptive immune responses, such as vaccines and adoptive CAR‐T cells, or to inhibit immunosuppressive molecules, such as immune checkpoint inhibitors or antibodies. The U.S Food and Drug Administration has approved Sipuleucel‐T for the treatment of asymptomatic or minimally symptomatic metastatic castrate‐resistant prostate cancer (mCRPC) and immune checkpoint inhibitor pembrolizumab for the treatment of all solid tumors, including prostate cancer, with impaired mismatch repair genes/microsatellite instability; however, the current clinical outcomes still need to be improved. As various immunosuppressive mechanisms coexist and cross‐interact within the tumor microenvironment, different immunotherapy approaches may have to be combined and selected in a highly personalized way. It is hoped that this rapidly evolving field of immunotherapy will achieve successful treatment for mCRPC and will be applied to a wider range of prostate cancer patients.

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The efficacy of PD-1/PD-L1 blockade in cold cancers and future perspectives

Cited by 157 publications

References 99 publications

Tumor-Infiltrating PD-1hiCD8+-T-Cell Signature as an Effective Biomarker for Immune Checkpoint Inhibitor Therapy Response Across Multiple Cancers

Tumor-Infiltrating PD-1hiCD8+-T-Cell Signature as an Effective Biomarker for Immune Checkpoint Inhibitor Therapy Response Across Multiple Cancers

Normalization in tumor ecosystem: Opportunities and challenges

Immunotherapy in treatment of metastatic prostate cancer: An approach to circumvent immunosuppressive tumor microenvironment

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