Tissue-Dependent Tumor Microenvironments and Their Impact on Immunotherapy Responses

Oliver, Amanda J.; Lau, Peter K. H.; Unsworth, Ashleigh; Loi, Sherene; Darcy, Phillip K.; Kershaw, Michael H.; Slaney, Clare Y.

doi:10.3389/fimmu.2018.00070

Cited by 128 publications

(125 citation statements)

References 78 publications

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“…There is growing evidence that the anatomical site of tumor growth can influence responses to immunotherapy . We evaluated responses to αPD‐1/αCTLA4 and trimAb (combination of agonistic antibodies against αDR5, α4‐1BB and αCD40) in breast tumors growing in mice in the MFP and common sites of breast cancer metastasis (liver and lungs).…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies investigating preclinical models of pancreatic, renal cell and prostate cancers showed distinct RNA profiles of tumors growing in different sites . To address this in our model, we performed 3’ RNA sequencing of tumors isolated from the MFP and lung.…”

Section: Resultsmentioning

confidence: 99%

“…Despite emerging evidence that the tissue of tumor growth impacts on therapy responses, our understanding of this influence is not fully defined. Here, we used a model of breast cancer to show that tumors growing in the lungs were less sensitive to two different immunotherapies compared with the same tumor growing in the MFP.…”

Section: Discussionmentioning

confidence: 99%

“…An emerging determinant of TME composition is the anatomical site of tumor growth . Evidence has recently emerged for the tumor location influencing the response of human tumors to immunotherapies, particularly to αPD‐1 and αPD‐1/αCTLA4 .…”

Section: Introductionmentioning

confidence: 99%

“…An emerging determinant of TME composition is the anatomical site of tumor growth. [10][11][12] Evidence has recently emerged for the tumor location influencing the response of human tumors to immunotherapies, particularly to aPD-1 and aPD-1/aCTLA4. [10][11][12] In particular, retrospective analysis has revealed reduced responses to checkpoint blockade in tumors in certain metastatic sites compared with primary tumors in melanoma, non-small-cell lung cancer (NSCLC), urothelial cancer and triple-negative breast cancer (TNBC).…”

Section: Introductionmentioning

confidence: 99%

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Tissue‐specific tumor microenvironments influence responses to immunotherapies

et al. 2019

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Objectives Investigation of variable response rates to cancer immunotherapies has exposed the immunosuppressive tumor microenvironment (TME) as a limiting factor of therapeutic efficacy. A determinant of TME composition is the tumor location, and clinical data have revealed associations between certain metastatic sites and reduced responses. Preclinical models to study tissue‐specific TMEs have eliminated genetic heterogeneity, but have investigated models with limited clinical relevance. Methods We investigated the TMEs of tumors at clinically relevant sites of metastasis (liver and lungs) and their impact on αPD‐1/αCTLA4 and trimAb (αDR5, α4‐1BB, αCD40) therapy responses in the 67NR mouse breast cancer and Renca mouse kidney cancer models. Results Tumors grown in the lungs were resistant to both therapies whereas the same tumor lines growing in the mammary fat pad (MFP), liver or subcutaneously could be completely eradicated, despite greater tumor burden. Assessment of tumor cells and drug delivery in 67NR lung or MFP tumors revealed no differences and prompted investigation into the immune TME. Lung tumors had a more immunosuppressive TME with increased myeloid‐derived suppressor cell infiltration, decreased T cell infiltration and activation, and decreased NK cell activation. Depletion of various immune cell subsets indicated an equivalent role for NK cells and CD8+ T cells in lung tumour control. Thus, targeting T cells with αPD‐1/αCTLA4 or trimAb was not sufficient to elicit a robust antitumor response in lung tumors. Conclusion Taken together, these data demonstrate that tissue‐specific TMEs influence immunotherapy responses and highlight the importance in defining tissue‐specific response patterns in patients.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tissue‐specific tumor microenvironments influence responses to immunotherapies

et al. 2019

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Nuclear Imaging of CAR T Immunotherapy to Solid Tumors: In Terms of Biodistribution, Viability, and Cytotoxic Effect

et al. 2023

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Immunotherapy has become a mainstay of cancer therapy. Since chimeric antigen receptor (CAR) T immunotherapy achieves unprecedented success in curing hematological malignancies, the possibility of it revolutionizing the paradigm of solid tumors has aroused increasing attention. However, the restricted accessibility to tumor parenchyma, the immunosuppressive tumor microenvironment, and antigen heterogeneity of solid tumors make it difficult to replicate its success. Therefore, dynamic evaluation of CAR T cells’ tumor accessibility, intratumoral viability, and anti‐tumor cytotoxicity is necessary to facilitate its translation to solid tumors. Besides, real‐timely imaging above events in vivo can help evaluate therapeutic responses and optimize CAR T immunotherapy for solid tumors. Nuclear imaging, including positron emission tomography (PET) and single‐photon emission computed tomography (SPECT) imaging, is frequently applied for evaluating adoptive cell therapies owing to its excellent sensitivity, high tissue penetration, and great translation potential. In addition, quantitative analysis can be performed in dynamic and noninvasive patterns. This review focuses on recent advances in PET/SPECT technologies and imaging probes in monitoring CAR T cells’ migration, viability, and cytotoxicity to solid tumors post‐administration. Prospects of what should be done in the next stage to promote CAR T therapy's application in solid tumors are also discussed.

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Bypassing the Immunosuppression of Myeloid‐Derived Suppressor Cells by Reversing Tumor Hypoxia Using a Platelet‐Inspired Platform

Zhang

Xia

Liu

et al. 2020

Adv Funct Materials

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Myeloid-derived suppressor cells (MDSCs) are garnering increasing attention given their role in tumor development. Herein, a nano-enabled strategy is demonstrated for the eradication of tumor-infiltrated MDSCs by reversing hypoxia. Oxygen-independent photodynamic bismuth tungstate nanoparticles (Bi 2 WO 6 NPs) are loaded into reactive oxygen species (ROS) responsive platelet membranes (PMs) to form a hybrid (PM-BiW NPs). P-Selectin on PMs endows PM-BiW NPs with selectivity toward cancer cells. Once in the tumor, laser illumination stimulates the Bi 2 WO 6 NPs photothermally and photodynamically, which produces enormous quantities of hydroxyl radicals. These hydroxyl radicals help rupture the PM and mitigate hypoxia with the assistance of ionizing radiation. This effectively remodels the tumor micro environment toward one disfavoring the recruitment of MDSCs and contributes to better prognosis. To better understand the mechanism, the expression levels of a set of markers are monitored. It is found that the downregulations of hypoxia-inducible factor-1α, ectonucleoside triphosphate diphosphohydrolase 2, and adenosine-5-phosphoricacid are behind the blocked infiltration of MDSCs. This platform strategy offers a promising approach to overcome the immunosuppression caused by MDSCs through a trimodal therapy integrating the power of photothermal and photodynamic therapy in addition to radiation therapy. Scheme 1. Working principle of PM-BiW NPs. In radical-free RT treatment, oxygen is essential for reaction with the broken end of DNA to augment the damage to an extent beyond the cells' repairing power. This leads to a deteriorated hypoxia condition that helps to recruit MDSCs and inhibits the function of CTLs. For PTT/PDT/RT treatment, in the presence of PM-BiW • OH radicals generated upon illumination can cause the destruction of ROS-responsive PM, followed by their release into cytosol where they behave as a sensitizer for irradiation. As the generation of • OH is fueled by H 2 O, there is no longer oxygen consumption. Thus, the tumor microenvironment is remodeled in such a way that the recruitment of MDSCs is disfavored. This also helps the CTLs respond to stress condition to act effectively against tumors.www.afm-journal.de www.advancedsciencenews.com (3 of 18)

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Tissue-Dependent Tumor Microenvironments and Their Impact on Immunotherapy Responses

Cited by 128 publications

References 78 publications

Tissue‐specific tumor microenvironments influence responses to immunotherapies

Tissue‐specific tumor microenvironments influence responses to immunotherapies

Nuclear Imaging of CAR T Immunotherapy to Solid Tumors: In Terms of Biodistribution, Viability, and Cytotoxic Effect

Bypassing the Immunosuppression of Myeloid‐Derived Suppressor Cells by Reversing Tumor Hypoxia Using a Platelet‐Inspired Platform

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