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Phototherapeutic Induction of Immunogenic Cell Death and CD8+ T Cell-Granzyme B Mediated Cytolysis in Human Lung Cancer Cells and Organoids.

ABSTRACT: Augmenting T cell mediated tumor killing via immunogenic cancer cell death (ICD) is the cornerstone of emerging immunotherapeutic approaches. We investigated the potential of methylene blue photodynamic therapy (MB-PDT) to induce ICD in human lung cancer. Non-Small Cell Lung Cancer (NSCLC) cell lines and primary human lung cancer organoids were evaluated in co-culture killing assays with MB-PDT and light emitting diodes (LEDs). ICD was characterised using immunoblotting, immunofluorescence, flow cytometry and confocal microscopy. Phototherapy with MB treatment and low energy LEDs decreased the proliferation of NSCLC cell lines inducing early necrosis associated with reduced expression of the anti-apoptotic protein, Bcl2 and increased expression of ICD markers, calreticulin (CRT), intercellular cell-adhesion molecule-1 (ICAM-1) and major histocompatibility complex I (MHC-I) in NSCLC cells. MB-PDT also potentiated CD8⁺ T cell-mediated cytolysis of lung cancer via granzyme B in lung cancer cells and primary human lung cancer organoids.

SUBMITTER: Valanciute A

PROVIDER: S-EPMC9454585 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Phototherapeutic Induction of Immunogenic Cell Death and CD8+ T Cell-Granzyme B Mediated Cytolysis in Human Lung Cancer Cells and Organoids.

Valančiūtė Asta A Mathieson Layla L O'Connor Richard A RA Scott Jamie I JI Vendrell Marc M Dorward David A DA Akram Ahsan R AR Dhaliwal Kevin K

Cancers 20220825 17

Augmenting T cell mediated tumor killing via immunogenic cancer cell death (ICD) is the cornerstone of emerging immunotherapeutic approaches. We investigated the potential of methylene blue photodynamic therapy (MB-PDT) to induce ICD in human lung cancer. Non-Small Cell Lung Cancer (NSCLC) cell lines and primary human lung cancer organoids were evaluated in co-culture killing assays with MB-PDT and light emitting diodes (LEDs). ICD was characterised using immunoblotting, immunofluorescence, flow ...[more]

PMID: 36077656

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Project description:Cyclooxygenase (COX) plays a crucial role in the "inflammogenesis of cancer", which leads to tumor progression, metastasis, and immunotherapy resistance. Therefore, reducing "inflammogenesis" by COX inhibition may be a key perspective for cancer therapy. However, the role of tumor-derived COX in the actions of COX inhibitors remains incompletely understood. In this study, applying "old drug new tricks" to repurpose 5-aminosalicylic acid (5-ASA), a COX inhibitor, we examined the effect of 5-ASA, alone or in combination with doxorubicin (DOX), in several cancer cell lines with different levels of COX expression. To facilitate the evaluation of the combination effect on tumors in vivo, a new micellar carrier based on PEG-b-PNHS polymer-conjugated 5-ASA (PASA) was developed to enhance codelivery of 5-ASA and DOX. Folate was also introduced to the polymer (folate-PEG-NH2-conjugated PASA (FASA)) to further improve delivery to tumors via targeting both tumor cells and tumor macrophages. An unprecedented high DOX loading capacity of 42.28% was achieved through various mechanisms of carrier/drug interactions. FASA was highly effective in targeting to and in inhibiting the growth of both 4T1.2 and CT26 tumors in BALB/c mice. However, FASA was more effective in CT26 tumor that has a high level of COX expression. Codelivery of DOX via PASA and FASA led to a further improvement in antitumor activity. Mechanistic studies suggest that inhibition of COX in vivo led to a more active tumor immune microenvironment. Interestingly, treatment with FASA led to upregulation of PD-1 on T cells, likely due to repressing the inhibitory effect of prostaglandin E2 (PGE2) on PD-1 expression on T cells. Combination of FASA/DOX with anti-PD-1 antibody led to a drastic improvement in the overall antitumor activity including regression of some established tumors at a suboptimal dose of FASA/DOX. Our data suggest that FASA/DOX may represent a new and effective immunochemotherapy for various types of cancers, particularly those cancers with high levels of COX expression.

Dataset Information

Phototherapeutic Induction of Immunogenic Cell Death and CD8+ T Cell-Granzyme B Mediated Cytolysis in Human Lung Cancer Cells and Organoids.

Publications

Phototherapeutic Induction of Immunogenic Cell Death and CD8+ T Cell-Granzyme B Mediated Cytolysis in Human Lung Cancer Cells and Organoids.

Similar Datasets

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