Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models

Martinez-Usatorre, Amaia; Kadioglu, Ece; Boivin, Gaël; Cianciaruso, Chiara; Guichard, A; Torchia, Bruno; Zangger, Nadine; Nassiri, Sina; Keklikoglou, Ioanna; Schmittnaegel, Martina; Meylan, Etienne; Palma, Michele De

doi:10.1126/scitranslmed.abd1616

Cited by 59 publications

(35 citation statements)

References 102 publications

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“…Similar findings were reported in mouse and human glioblastoma 29 . In apparent contrast to these studies, in lung cancer models, both TRM and monocyte-derived TAMs contributed to generating an immunosuppressive TME in early stages by sustaining regulatory T cells 30 . Perhaps unexpectedly, macrophages in early-stage human lung cancer did not exert immunosuppressive functions 31 .…”

Section: Tam Diversity and Prognosismentioning

confidence: 69%

Macrophages as tools and targets in cancer therapy

Mantovani

Allavena

Marchesi

et al. 2022

Nat Rev Drug Discov

717

508

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Tumour-associated macrophages are an essential component of the tumour microenvironment and have a role in the orchestration of angiogenesis, extracellular matrix remodelling, cancer cell proliferation, metastasis and immunosuppression, as well as in resistance to chemotherapeutic agents and checkpoint blockade immunotherapy. Conversely, when appropriately activated, macrophages can mediate phagocytosis of cancer cells and cytotoxic tumour killing, and engage in effective bidirectional interactions with components of the innate and adaptive immune system. Therefore, they have emerged as therapeutic targets in cancer therapy. Macrophage-targeting strategies include inhibitors of cytokines and chemokines involved in the recruitment and polarization of tumour-promoting myeloid cells as well as activators of their antitumorigenic and immunostimulating functions. Early clinical trials suggest that targeting negative regulators (checkpoints) of myeloid cell function indeed has antitumor potential. Finally, given the continuous recruitment of myelomonocytic cells into tumour tissues, macrophages are candidates for cell therapy with the development of chimeric antigen receptor effector cells. Macrophage-centred therapeutic strategies have the potential to complement, and synergize with, currently available tools in the oncology armamentarium.

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Section: Tam Diversity and Prognosismentioning

confidence: 69%

Macrophages as tools and targets in cancer therapy

Mantovani

Allavena

Marchesi

et al. 2022

Nat Rev Drug Discov

717

508

View full text Add to dashboard Cite

show abstract

“…Dual inhibition of TAMs with CSF1R inhibitors and cisplatin suppresses Tregs, which redirect anti-PD-1 antibodies to CD8 + T cells. As a result, immunotherapy with antiangiogenic drugs exerts an excellent efficacy to eradicate cancer lesions in most cases [ 206 ].…”

Section: Advances In Pd-1/pd-l1 Blockade-based Combination Treatment ...mentioning

confidence: 99%

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

et al. 2022

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Immune checkpoint molecules are promising anticancer targets, among which therapeutic antibodies targeting the PD-1/PD-L1 pathway have been widely applied to cancer treatment in clinical practice and have great potential. However, this treatment is greatly limited by its low response rates in certain cancers, lack of known biomarkers, immune-related toxicity, innate and acquired drug resistance, etc. Overcoming these limitations would significantly expand the anticancer applications of PD-1/PD-L1 blockade and improve the response rate and survival time of cancer patients. In the present review, we first illustrate the biological mechanisms of the PD-1/PD-L1 immune checkpoints and their role in the healthy immune system as well as in the tumor microenvironment (TME). The PD-1/PD-L1 pathway inhibits the anticancer effect of T cells in the TME, which in turn regulates the expression levels of PD-1 and PD-L1 through multiple mechanisms. Several strategies have been proposed to solve the limitations of anti-PD-1/PD-L1 treatment, including combination therapy with other standard treatments, such as chemotherapy, radiotherapy, targeted therapy, anti-angiogenic therapy, other immunotherapies and even diet control. Downregulation of PD-L1 expression in the TME via pharmacological or gene regulation methods improves the efficacy of anti-PD-1/PD-L1 treatment. Surprisingly, recent preclinical studies have shown that upregulation of PD-L1 in the TME also improves the response and efficacy of immune checkpoint blockade. Immunotherapy is a promising anticancer strategy that provides novel insight into clinical applications. This review aims to guide the development of more effective and less toxic anti-PD-1/PD-L1 immunotherapies.

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“… 31 , 32 The PD-1/PD-L1 signaling pathway leads to exhaustion and functional inhibition of T cells, which is currently the main immunotherapy target. 14 , 33 , 34 Therefore, after efferocytosis, the PD-L1 expression on tumor-associated macrophages is worthy of attention. However, it is unclear how efferocytosis impacts the expression of PD-L1, as well as the tumor growth and immune landscape of osteosarcoma.…”

Section: Introductionmentioning

confidence: 99%

MerTK-mediated efferocytosis promotes immune tolerance and tumor progression in osteosarcoma through enhancing M2 polarization and PD-L1 expression

Lin

Jin

et al. 2022

OncoImmunology

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The poor progress of immunotherapy on osteosarcoma patients requires deeper delineation of immune tolerance mechanisms in the osteosarcoma microenvironment and a new therapeutic strategy. Clearance of apoptotic cells by phagocytes, a process termed “efferocytosis,” is ubiquitous in tumors and mediates the suppression of innate immune inflammatory response. Considering the massive infiltrated macrophages in osteosarcoma, efferocytosis probably serves as a potential target, but is rarely studied in osteosarcoma. Here, we verified M2 polarization and PD-L1 expression of macrophages following efferocytosis. Pharmacological inhibition and genetic knockdown were used to explore the underlying pathway. Moreover, tumor progression and immune landscape were evaluated following inhibition of efferocytosis in osteosarcoma model. Our study indicated that efferocytosis promoted PD-L1 expression and M2 polarization of macrophages. Ëfferocytosis was mediated by MerTK receptor in osteosarcoma and regulated the phenotypes of macrophages through the p38/STAT3 pathway. By establishing the murine osteosarcoma model, we emphasized that inhibition of MerTK suppressed tumor growth and enhanced the T cell cytotoxic function by increasing the infiltration of CD8 + T cells and decreasing their exhaustion. Our findings demonstrate that MerTK-mediated efferocytosis promotes osteosarcoma progression by enhancing M2 polarization of macrophages and PD-L1-induced immune tolerance, which were regulated through the p38/STAT3 pathway.

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Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models

Cited by 59 publications

References 102 publications

Macrophages as tools and targets in cancer therapy

Macrophages as tools and targets in cancer therapy

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

MerTK-mediated efferocytosis promotes immune tolerance and tumor progression in osteosarcoma through enhancing M2 polarization and PD-L1 expression

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