The future of cancer immunotherapy: microenvironment-targeting combinations

Murciano‐Goroff, Yonina R.; Warner, Allison Betof; Wolchok, Jedd D.

doi:10.1038/s41422-020-0337-2

Cited by 548 publications

(471 citation statements)

References 194 publications

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“…This phenomenon has been reported to play a role in regulatory T cell (Treg) suppressive function creating a tolerizing microenvironment for tumor growth. ICIs directed to LAG-3 have been shown to have synergy with PD-1 inhibition in mouse models, suggesting that co-signaling blockade could restore a favorable immune microenvironment that can respond to antigenic stimulation [ 224 ].…”

Section: Role Of Hla As a Predictive Biomarker For Ici-based Immunmentioning

confidence: 99%

Role of Human Leukocyte Antigen System as A Predictive Biomarker for Checkpoint-Based Immunotherapy in Cancer Patients

Sabbatino

Liguori

Polcaro

et al. 2020

IJMS

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Recent advances in cancer immunotherapy have clearly shown that checkpoint-based immunotherapy is effective in a small subgroup of cancer patients. However, no effective predictive biomarker has been identified so far. The major histocompatibility complex, better known in humans as human leukocyte antigen (HLA), is a very polymorphic gene complex consisting of more than 200 genes. It has a crucial role in activating an appropriate host immune response against pathogens and tumor cells by discriminating self and non-self peptides. Several lines of evidence have shown that down-regulation of expression of HLA class I antigen derived peptide complexes by cancer cells is a mechanism of tumor immune escape and is often associated to poor prognosis in cancer patients. In addition, it has also been shown that HLA class I and II antigen expression, as well as defects in the antigen processing machinery complex, may predict tumor responses in cancer immunotherapy. Nevertheless, the role of HLA in predicting tumor responses to checkpoint-based immunotherapy is still debated. In this review, firstly, we will describe the structure and function of the HLA system. Secondly, we will summarize the HLA defects and their clinical significance in cancer patients. Thirdly, we will review the potential role of the HLA as a predictive biomarker for checkpoint-based immunotherapy in cancer patients. Lastly, we will discuss the potential strategies that may restore HLA function to implement novel therapeutic strategies in cancer patients.

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Section: Role Of Hla As a Predictive Biomarker For Ici-based Immunmentioning

confidence: 99%

Role of Human Leukocyte Antigen System as A Predictive Biomarker for Checkpoint-Based Immunotherapy in Cancer Patients

Sabbatino

Liguori

Polcaro

et al. 2020

IJMS

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“…TME plays an important role in regulation of tumor immunogenicity [146], tumor progression, invasion, and metastasis [3,147]. In particular, the neutrophil-tumor interaction was shown to promote tumor cell invasion, increasing metastatic potential of cancer cells [45].…”

Section: Resultsmentioning

confidence: 99%

“…The invasion and metastasis processes of lung cancer cells may depend on many factors in TME, including immune cells and their cytokines and chemokines [50,148]. Therefore, targeting players in TME including TANs [149] as a therapeutic approach has become more and more important [146,150].…”

Section: Resultsmentioning

confidence: 99%

Role of neutrophil extracellular traps in regulation of lung cancer invasion and metastasis: Structural Insights from a Computational Model

Lee

Lawler

et al. 2020

Preprint

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Lung cancer is one of the leading causes of cancer-related deaths worldwide and is characterized by hijacking immune system for active growth and aggressive metastasis. Neutrophils, which in their original form should establish immune activities to the tumor as a first line of defense, are undermined by tumor cells to promote tumor invasion in several ways. In this study, we investigate the mutual interactions between the tumor cells and the neutrophils that facilitate tumor invasion by developing a mathematical model that involves taxis-reaction-diffusion equations for the critical components in the interaction. These include the densities of tumor and neutrophils, and the concentrations of signaling molecules and structure such as neutrophil extracellular traps (NETs). We apply the mathematical model to a Boyden invasion assay used in the experiments to demonstrate that the tumor-associated neutrophils can enhance tumor cell invasion by secreting the neutrophil elastase. We show that the model can both reproduce the major experimental observation on NET-mediated cancer invasion and make several important predictions to guide future experiments with the goal of the development of new anti-tumor strategies. Moreover, using this model, we investigate the fundamental mechanism of NET-mediated invasion of cancer cells and the impact of internal and external heterogeneity on the migration patterning of tumour cells and their response to different treatment schedules.

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“…Our current work demonstrates the upregulation of both IRF1 and PD-L1 following PARPi treatment of Ewing sarcoma cells. The upregulation of the checkpoint protein PD-L1 promotes an immunosuppressive tumor microenvironment, thus sheltering tumor cells from immune surveillance[31,32]. Our work suggests a possible mechanism whereby Ewing cells surviving PARPi-induced DNA damage can be reprogrammed to survive through the immune-protection imparted by upregulation of the IRF1 pathway.…”

mentioning

confidence: 76%

PARP inhibition in Ewing sarcoma: impact of germline DNA damage repair defects and activation of immunoregulatory pathways

Maurer¹,

Venier

Mukherjee³

et al. 2020

Preprint

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Ewing sarcoma, an oncofusion-driven primary bone tumor, can occur in the setting of various germline mutations in DNA damage repair pathway genes. We recently reported our discovery of a germline mutation in the DNA damage repair protein BARD1 (BRCA1-associated RING domain-1) in a patient with Ewing sarcoma. BARD1 is recruited to the site of DNA double stranded breaks via the poly(ADP-ribose) polymerase (PARP) protein and plays a critical role in DNA damage response pathways including homologous recombination. PARP inhibitors (PARPi) are effective against Ewing sarcoma cells in vitro, though have demonstrated limited success in clinical trials to date. In order to assess the impact of BARD1 loss on Ewing sarcoma sensitivity to PARP inhibitor therapy, we generated the novel PSaRC318 patient-derived Ewing tumor cell from our patient with a germline BARD1 mutation and then analyzed the response of these cells to PARPi. We demonstrate that PSaRC318 cells are sensitive to PARP inhibition and by testing the effect of BARD1 depletion in additional Ewing sarcoma cell lines, we confirm that loss of BARD1 enhances PARPi sensitivity. In certain malignancies, DNA damage can activate the IRF1 (interferon response factor 1) immunoregulatory pathway, and the activation of this pathway can drive immunosuppression through upregulation of the immune checkpoint protein PD-L1. In order to determine the ability of PARPi to alter Ewing tumor immunoregulation, we evaluated whether PARPi results in upregulation of the IRF1-PDL1 pathway. Indeed, we now demonstrate that PARPi leads to increased PD-L1 expression in Ewing sarcoma. Together, these data thus far suggest that while Ewing tumors harboring germline mutations in DNA damage repair proteins may in respond to PARPi in vitro, in vivo benefit of PARPi may only be demonstrated when counteracting the immunosuppressive effects of DNA damage by concurrently targeting immune checkpoint proteins.

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The future of cancer immunotherapy: microenvironment-targeting combinations

Cited by 548 publications

References 194 publications

Role of Human Leukocyte Antigen System as A Predictive Biomarker for Checkpoint-Based Immunotherapy in Cancer Patients

Role of Human Leukocyte Antigen System as A Predictive Biomarker for Checkpoint-Based Immunotherapy in Cancer Patients

Role of neutrophil extracellular traps in regulation of lung cancer invasion and metastasis: Structural Insights from a Computational Model

PARP inhibition in Ewing sarcoma: impact of germline DNA damage repair defects and activation of immunoregulatory pathways

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