Tumor microenvironment changes leading to resistance of immune checkpoint inhibitors in metastatic melanoma and strategies to overcome resistance

Pulluri, Bhargavi; Kumar, Abhijeet; Shaheen, Montaser; Jeter, Joanne; Sundararajan, Srinath

doi:10.1016/j.phrs.2017.07.006

Cited by 53 publications

(35 citation statements)

References 63 publications

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“…in metastatic melanoma), a majority of patients still fail to respond. Biologic and molecular mechanisms of 65 intrinsic and acquired resistance to ICI are under intense investigation, but the causes of patient non-response still remain largely unknown (Kelderman et al 2014;Pulluri et al 2017). There are ongoing efforts to discover pre-treatment biomarkers of response to ICI, as this would allow for the identification of patients that are most likely to respond, and consequently prevent other patients from unnecessary immune-related adverse events (Sharma & Allison 2015).…”

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confidence: 99%

Predicting tumour response to anti-PD-1 immunotherapy with computational modelling

et al. 2019

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Cancer immunotherapy is a rapidly developing field, with numerous drugs and 15 therapy combinations waiting to be tested in pre-clinical and clinical settings. However, the costly and time-consuming trial-and-error approach to development of new treatment paradigms creates a research bottleneck, motivating the development of complementary approaches. Computational modelling is a compelling candidate for this task, however, difficulties associated with the validation of such models limits their use in pre-clinical 20 and clinical settings. Here we propose a bottom-up deterministic computational model to simulate tumour response to treatment with anti-programmed-death-1 antibodies (anti-PD-1). The model was built with validation in mind, and so contains minimum number of parameters, and only 4 free parameters. Moreover, all model parameters can be measured experimentally. Free parameters were tuned by fitting the model to 25 experimental data from the literature, using B16-F10 murine melanoma implanted into wild type (C57BL/6), as well as into immunodeficient (NSG) mice strains, and treated with anti-PD-1 antibodies. The model's predictive ability was verified on two independent datasets from literature with different but well-known inputs. To identify possible biomarkers of response to anti-PD-1 immunotherapy, sensitivity study of key model 30 parameters was performed. Good agreement between the simulated tumour growth curves and the experimental data was achieved, with mean relative deviations in the range of 13

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confidence: 99%

Predicting tumour response to anti-PD-1 immunotherapy with computational modelling

et al. 2019

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“…In vivo melanoma tumors were induced by subcutaneous inoculation of 10 6 B16.F10 cells in the right flank of 6-8 weeks-old male C57Bl/6 mice (Cantacuzino Institute, Bucharest, Romania). Treatments started at day 11 after cell inoculation when tumors were about 100 mm 3 . Experiments were performed according to the national regulations and were approved by the Babes-Bolyai University Ethics Committee (Cluj-Napoca, Romania, Project ID: PN-III-P4-ID-PCE-2016-0342 No.91/2017, Approval no.…”

Section: In Vivo Melanoma Modelmentioning

confidence: 99%

“…Metastatic melanoma has a poor prognosis, mainly due to the tumor aggressiveness and rapid development of cancer cell resistance to both chemotherapy and immunotherapy, as well to the new generation tumor-targeted drugs [2]. Moreover, clinical and experimental data have demonstrated the critical role of the tumor microenvironment (TME) in the settlement of drug resistance of cancer cells as well as in inducing the immune non-responsiveness at the tumor site [3,4]. Primarily, tumor cells induced a proneoplastic TME via the creation of an immunosuppressive niche by the selective recruitment of regulatory T cells and the polarization of the tumor-associated macrophages (TAMs) to an alternative, protumor phenotype (M2 macrophages) [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Overcoming Intrinsic Doxorubicin Resistance in Melanoma by Anti-Angiogenic and Anti-Metastatic Effects of Liposomal Prednisolone Phosphate on Tumor Microenvironment

Licărete

Rauca

Lupuţ

et al. 2020

IJMS

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Regardless of recent progress, melanoma is very difficult to treat, mainly due to the drug resistance modulated by tumor cells as well as by the tumor microenvironment (TME). Among the immune cells recruited at the tumor site, tumor associated macrophages (TAMs) are the most abundant, promoting important tumorigenic processes: angiogenesis, inflammation and invasiveness. Furthermore, it has been shown that TAMs are involved in mediating the drug resistance of melanoma cells. Thus, in the present study, we used liposomal formulation of prednisolone disodium phosphate (LCL-PLP) to inhibit the protumor function of TAMs with the aim to sensitize the melanoma cells to the cytotoxic drug doxorubicin (DOX) to which human melanoma has intrinsic resistance. Consequently, we evaluated the in vivo effects of the concomitant administration of LCL-PLP and liposomal formulation of DOX (LCL-DOX) on B16.F10 melanoma growth and on the production of key molecular markers for tumor development. Our results demonstrated that the concomitant administration of LCL-PLP and LCL-DOX induced a strong inhibition of tumor growth, primarily by inhibiting TAMs-mediated angiogenesis as well as the tumor production of MMP-2 and AP-1. Moreover, our data suggested that the combined therapy also affected TME as the number of infiltrated macrophages in melanoma microenvironment was reduced significantly.

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“…Although amazing outcomes are observed in checkpoint immunotherapy, a large proportion of patients failed to respond to immune checkpoint blockades which reinforces the need for alternative approaches for these patients (Ghahremanloo, Soltani, Modaresi, & Hashemy, 2019; Pulluri, Kumar, Shaheen, Jeter, & Sundararajan, 2017). In the new era of medicine, there is much focus on the synergistic combinations of immunotherapies to augment immune outcomes (Melero et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Cytokines as potential combination agents with PD‐1/PD‐L1 blockade for cancer treatment

Mohammad

Ghahremanloo

Soltani

et al. 2020

Journal Cellular Physiology

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Immunotherapy has caused a paradigm shift in the treatment of several malignancies, particularly the blockade of programmed death‐1 (PD‐1) and its specific receptor/ligand PD‐L1 that have revolutionized the treatment of a variety of malignancies, but significant durable responses only occur in a small percentage of patients, and other patients failed to respond to the treatment. Even those who initially respond can ultimately relapse despite maintenance treatment, there is considerable potential for synergistic combinations of immunotherapy and chemotherapy agents with immune checkpoint inhibitors into conventional cancer treatments. The clinical experience in the use of cytokines in the clinical setting indicated the efficiency of cytokine therapy in cancer immunotherapy. Combinational approaches to enhancing PD‐L1/PD‐1 pathways blockade efficacy with several cytokines such as interleukin (IL)‐2, IL‐15, IL‐21, IL‐12, IL‐10, and interferon‐α (IFN‐α) may result in additional benefits. In this review, the current state of knowledge about PD‐1/PD‐L1 inhibitors, the date in the literature to ascertain the combination of anti‐PD‐1/PD‐L1 antibodies with cytokines is discussed. Finally, it is noteworthy that novel therapeutic approaches based on the efficient combination of recombinant cytokines with the PD‐L1/PD‐1 blockade therapy can enhance antitumor immune responses against various malignancies.

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Tumor microenvironment changes leading to resistance of immune checkpoint inhibitors in metastatic melanoma and strategies to overcome resistance

Cited by 53 publications

References 63 publications

Predicting tumour response to anti-PD-1 immunotherapy with computational modelling

Predicting tumour response to anti-PD-1 immunotherapy with computational modelling

Overcoming Intrinsic Doxorubicin Resistance in Melanoma by Anti-Angiogenic and Anti-Metastatic Effects of Liposomal Prednisolone Phosphate on Tumor Microenvironment

Cytokines as potential combination agents with PD‐1/PD‐L1 blockade for cancer treatment

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