Cancer immunotherapy resistance based on immune checkpoints inhibitors: Targets, biomarkers, and remedies

Pérez-Ruiz, Elísabeth; Melero, Ignacio; Kopecka, Joanna; Sarmento‐Ribeiro, Ana Bela; García-Aranda, Marilina; Rivas, Javier De Las

doi:10.1016/j.drup.2020.100718

Cited by 132 publications

(103 citation statements)

References 113 publications

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“…One of the key reasons for that was the obstruction of the TME which consisted of complicated cellular and molecular components (Chae et al, 2018;Seidel et al, 2018;Yang et al, 2019b;Lei et al, 2020). Recent evidences reveal that TAMs are the most abundant infiltrating immunosuppressive cells in the TME, playing a key role influencing efficacy of anti-tumor immunotherapy (Pérez-Ruiz et al, 2020). Therefore, understanding specific molecular mechanisms by which TAMs affect tumor immunotherapy is of great value for developing ideal treatment strategies for LUAD patients.…”

Section: Discussionmentioning

confidence: 99%

Identification of a ceRNA Network in Lung Adenocarcinoma Based on Integration Analysis of Tumor-Associated Macrophage Signature Genes

Zhang

et al. 2021

Front. Cell Dev. Biol.

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As research into tumor-immune interactions progresses, immunotherapy is becoming the most promising treatment against cancers. The tumor microenvironment (TME) plays the key role influencing the efficacy of anti-tumor immunotherapy, in which tumor-associated macrophages (TAMs) are the most important component. Although evidences have emerged revealing that competing endogenous RNAs (ceRNAs) were involved in infiltration, differentiation and function of immune cells by regulating interactions among different varieties of RNAs, limited comprehensive investigation focused on the regulatory mechanism between ceRNA networks and TAMs. In this study, we aimed to utilize bioinformatic approaches to explore how TAMs potentially influence the prognosis and immunotherapy of lung adenocarcinoma (LUAD) patients. Firstly, according to TAM signature genes, we constructed a TAM prognostic risk model by the least absolute shrinkage and selection operator (LASSO) cox regression in LUAD patients. Then, differential gene expression was analyzed between high- and low-risk patients. Weighted gene correlation network analysis (WGCNA) was utilized to identify relevant gene modules correlated with clinical characteristics and prognostic risk score. Moreover, ceRNA networks were built up based on predicting regulatory pairs in differentially expressed genes. Ultimately, by synthesizing information of protein-protein interactions (PPI) analysis and survival analysis, we have successfully identified a core regulatory axis: LINC00324/miR-9-5p (miR-33b-5p)/GAB3 (IKZF1) which may play a pivotal role in regulating TAM risk and prognosis in LUAD patients. The present study contributes to a better understanding of TAMs associated immunosuppression in the TME and provides novel targets and regulatory pathway for anti-tumor immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Identification of a ceRNA Network in Lung Adenocarcinoma Based on Integration Analysis of Tumor-Associated Macrophage Signature Genes

Zhang

et al. 2021

Front. Cell Dev. Biol.

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“…Although the remarkable benefits of immunotherapy are evident, evidence from recent studies demonstrated that ICIs are associated with acquired or innate resistance ( 23 ). Immunotherapy focuses on harnessing the immune system to target and eradicate malignant cells.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Immune Infiltration and Construction of a Prediction Model for Overall Survival in Melanoma Patients

Zhu

Liu

2021

Front. Oncol.

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Reports indicate that the use of anti-programmed cell death-1 (PD-1) and death ligand-1 (PD-L1) monoclonal antibodies for the treatment of patients diagnosed with melanoma has demonstrated promising efficacy. Nonetheless, this therapy is limited by the resistance induced by the tumor microenvironment (TME). As such, understanding the complexity of the TME is vital in enhancing the efficiency of immunotherapy. This study used four different methods to estimate the infiltrating level of immune cells. Besides, we analyzed their infiltration pattern in primary and metastatic melanoma obtained from The Cancer Genome Atlas (TCGA) database. As a consequence, we discovered a significantly higher infiltration of immune cells in metastatic melanoma compared to primary tumor. Consensus clustering identified four clusters in melanoma with different immune infiltration and clusters with higher immune infiltration demonstrated a better overall survival. To elucidate the underlying mechanisms of immune cell infiltration, the four clusters were subdivided into two subtypes denoted as hot and cold tumors based on immune infiltration and predicted immune response. Enrichment analysis of differentially expressed genes (DEGs) revealed different transcriptome alterations in two types of tumors. Additionally, we found tyrosinase-related protein1 (TYRP1) was negatively correlated with CD8A expression. In vitro experiments showed that knockdown TYRP1 promoted the expression of HLA-A, B, and C. Eventually, we constructed a prediction model which was validated in our external cohort. Notably, this model also performed effectively in predicting the survival of patients under immunotherapy. In summary, this work provides a deeper understanding of the state of immune infiltration in melanoma and a prediction model that might guide the clinical treatment of patients with melanoma.

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“…In this work, we have demonstrated that HC-AdVs can be employed to achieve controlled and sustained expression of aPD-L1, resulting in a significant antitumor effect in a subcutaneous colorectal cancer model. However, the efficacy of ICIs targeting the PD-1/PD-L1 axis depends not only on the intrinsic characteristics of tumor cells but also on compensatory mechanisms and on the composition of the TME [3,12]. We show here that the same type of tumor becomes largely insensitive to aPD-L1 expression when it grows as a rapidly progressing PC, in contrast with the subcutaneous nodules.…”

Section: Discussionmentioning

confidence: 73%

“…These immune checkpoint inhibitors (ICIs) have improved the management of patients suffering from advanced melanoma [6], renal and urothelial cancers [7], non-small cell lung cancer [8], head and neck squamous cell carcinoma [9], Merkel cell carcinoma [10] and Hodgkin's lymphoma [11]. However, less than 40% of patients obtain a clinical benefit from these treatments, due to primary or secondary resistances [3,12]. This is the case of colorectal cancer, in which only a minority of cases with high microsatellite instability and/or a high immunoscore are clear candidates for ICIs [13,14].…”

Section: Introductionmentioning

confidence: 99%

Adenovirus-Mediated Inducible Expression of a PD-L1 Blocking Antibody in Combination with Macrophage Depletion Improves Survival in a Mouse Model of Peritoneal Carcinomatosis

Buñuales

Ballesteros-Briones

González-Aparicio

et al. 2021

IJMS

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Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a growing number of malignancies. However, overcoming primary or secondary resistances is difficult due to pharmacokinetics issues and side effects associated with high systemic exposure. Local or regional expression of monoclonal antibodies (mAbs) using gene therapy vectors can alleviate this problem. In this work, we describe a high-capacity adenoviral vector (HCA-EFZP-aPDL1) equipped with a mifepristone-inducible system for the controlled expression of an anti-programmed death ligand 1 (PD-L1) blocking antibody. The vector was tested in an immune-competent mouse model of colorectal cancer based on implantation of MC38 cells. A single local administration of HCA-EFZP-aPDL1 in subcutaneous lesions led to a significant reduction in tumor growth with minimal release of the antibody in the circulation. When the vector was tested in a more stringent setting (rapidly progressing peritoneal carcinomatosis), the antitumor effect was marginal even in combination with other immune-stimulatory agents such as polyinosinic-polycytidylic acid (pI:C), blocking mAbs for T cell immunoglobulin, mucin-domain containing-3 (TIM-3) or agonistic mAbs for 4-1BB (CD137). In contrast, macrophage depletion by clodronate liposomes enhanced the efficacy of HCA-EFZP-aPDL1. These results highlight the importance of addressing macrophage-associated immunoregulatory mechanisms to overcome resistance to ICIs in the context of colorectal cancer.

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Cancer immunotherapy resistance based on immune checkpoints inhibitors: Targets, biomarkers, and remedies

Cited by 132 publications

References 113 publications

Identification of a ceRNA Network in Lung Adenocarcinoma Based on Integration Analysis of Tumor-Associated Macrophage Signature Genes

Identification of a ceRNA Network in Lung Adenocarcinoma Based on Integration Analysis of Tumor-Associated Macrophage Signature Genes

Characterization of Immune Infiltration and Construction of a Prediction Model for Overall Survival in Melanoma Patients

Adenovirus-Mediated Inducible Expression of a PD-L1 Blocking Antibody in Combination with Macrophage Depletion Improves Survival in a Mouse Model of Peritoneal Carcinomatosis

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