腫瘍と免疫細胞の相互作用に関するLLNLの研究が、がん免疫療法に影響を及ぼす可能性(LLNL study on tumor/immune cell interaction could impact cancer immunotherapies)

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2022-03-16 ローレンスリバモア国立研究所(LLNL)

ローレンス・リバモア国立研究所(LLNL)は、がん細胞と臓器の「足場」である細胞外マトリックス(ECM)との相互作用を研究していましたが、ECM内のタンパク質が免疫系による腫瘍の殺傷能力に劇的な影響を与えることを発見しました。この研究結果は、Biomaterials誌オンライン版に掲載され、多くの乳がんに見られる免疫抑制を研究するための新しいアプローチであり、がんに対する免疫系を活性化する新しい経路を開く可能性がある、と研究者らは述べています。
Lawrence Livermore National Laboratory (LLNL) scientists exploring the interaction between cancer cells and the extracellular matrix (ECM) — the “scaffolding” of organs — found that proteins in the ECM can dramatically impact the immune system’s ability to kill tumors. Researchers said the findings, published online in the journal Biomaterials, could represent a novel approach to studying immunosuppression found in many breast cancers and open new pathways of activating the immune system to target cancer.

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LLNL study on tumor/immune cell interaction could impact cancer immunotherapies
Lawrence Livermore National Laboratory (LLNL) scientists exploring the interaction between cancer cells and the extracel...
ScienceDirect

細胞外マトリックスはin vitroにおけるT細胞による悪性腫瘍のクリアランスを調節する Extracellular matrix modulates T cell clearance of malignant cells in vitro

ClaireRobertsonaAimySebastianbAubreeHinckleybNaiomy D.Rios-ArcebWilliam F.HynesaSkye A.EdwardsaeWeiHebNicholas R.HumbElizabeth K.WheeleraGabriela G.LootsbcMatthew A.ColemanbdMonica L.Moyaa

Abstract

Despite the success of T cell checkpoint therapies, breast cancers rarely express these immunotherapy markers and are believed to be largely “immune cold” with limited inflammation and immune activation. The reason for this limited immune activation remains poorly understood. We sought to determine whether extracellular matrix substrate could contribute to this limited immune activation. Specifically, we asked whether extracellular matrix could alter T cell cytotoxicity against malignant mammary gland carcinoma cells (MCC) in a setup designed to promote maximal T cell efficacy (i.e., rich media with abundant IL2, high ratio of T cells to MCC). We observed that T cell clearance of MCC varied from 0% in collagen 4 or 6 conditions to almost 100% in fibronectin or vitronectin. Transcriptomics revealed that T cell function was defective in MCC/T cell cocultures on collagen 4 (Col4), potentially corresponding to greater expression of cytokines MCC cultured in this environment. In contrast, transcriptomics revealed an effective, exhausted phenotype on vitronectin. The observation that Col4 induces T cell suppression suggests that targeting tumor-ECM interactions may permit new approaches for utilizing immunotherapy in tumors which do not provoke a strong immune response.

Graphical abstract

We studied clearance of malignant cells by strain mismatched T cells in a microenvironmental microarray. We observed a stark difference in clearance of malignant cells cultured in different environments, which we correlated to altered expression of T cell differentiation markers, chemokines and other immunosuppressive factors in different ECM conditions.

腫瘍と免疫細胞の相互作用に関するLLNLの研究が、がん免疫療法に影響を及ぼす可能性(LLNL study on tumor/immune cell interaction could impact cancer immunotherapies)

 

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