Adaptive meets innate: CD8+ T cells kill MHC-I-negative tumour cells

Peeters, Bas W.A.; Gillespie, Geraldine M.

doi:10.1038/s41577-023-00872-y

Cited by 2 publications

(2 citation statements)

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“…This mechanism is particularly active and effective against MHC-I-loss variants and is mediated instead by T cell NKG2D engagement of non-classical MHC-I (NKG2DLs) on tumor cells in an antigen-independent and indiscriminate fashion. Subsequent tumor cell killing depends on prior TCR-mediated T cell activation (even if by an ultimately tumor-irrelevant antigen), meaning that adaptive priming is then paired with subsequent innate killing 40 . Cell killing itself appears to involve cytotoxic degranulation with granzyme and perforin.…”

Section: Discussionmentioning

confidence: 99%

CD8+ T cells maintain killing of MHC-I-negative tumor cells through the NKG2D–NKG2DL axis

et al. 2023

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The accepted paradigm for both cellular and anti-tumor immunity relies upon tumor cell killing by CD8+ T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex (MHC) class I (MHC-I) molecules. Likewise, a classically described mechanism of tumor immune escape is tumor MHC-I downregulation. Here, we report that CD8+ T cells maintain the capacity to kill tumor cells that are entirely devoid of MHC-I expression. This capacity proves to be dependent instead on interactions between T cell natural killer group 2D (NKG2D) and tumor NKG2D ligands (NKG2DLs), the latter of which are highly expressed on MHC-loss variants. Necessarily, tumor cell killing in these instances is antigen independent, although prior T cell antigen-specific activation is required and can be furnished by myeloid cells or even neighboring MHC-replete tumor cells. In this manner, adaptive priming can beget innate killing. These mechanisms are active in vivo in mice as well as in vitro in human tumor systems and are obviated by NKG2D knockout or blockade. These studies challenge the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape and instead identify the NKG2D–NKG2DL axis as a therapeutic target for enhancing T cell-dependent anti-tumor immunity against MHC-loss variants.

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Section: Discussionmentioning

confidence: 99%

CD8+ T cells maintain killing of MHC-I-negative tumor cells through the NKG2D–NKG2DL axis

et al. 2023

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“…The effectiveness of ICB is based on the presence of infiltrated T cells in the tumor microenvironment. Hence, tumors with low infiltrated T cells, also known as “cold” tumors, respond poorly to ICB ( 9 ). Generally, immune “cold” tumors have four main characteristics: 1) low tumor immunogenicity, 2) defects in tumor antigen processing and presentation mechanisms, 3) insufficient infiltration of T cells, and 4) an immunosuppressive tumor microenvironment ( 10 – 13 ).…”

Section: Introductionmentioning

confidence: 99%

Photothermally sensitive gold nanocage augments the antitumor efficiency of immune checkpoint blockade in immune “cold” tumors

Xiao,

Zhao,

Wang

et al. 2023

Front. Immunol.

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IntroductionImmune checkpoint blockade (ICB) has revolutionized the therapy landscape of malignancy melanoma. However, the clinical benefits from this regimen remain limited, especially in tumors lacking infiltrated T cells (known as “cold” tumors). Nanoparticle-mediated photothermal therapy (PTT) has demonstrated improved outcomes in the ablation of solid tumors by inducing immunogenic cell death (ICD) and reshaping the tumor immune microenvironment. Therefore, the combination of PTT and ICB is a promising regimen for patients with “cold” tumors.MethodsA second near-infrared (NIR-II) light-activated gold nanocomposite AuNC@SiO2@HA with AuNC as a kernel, silica as shell, and hyaluronic acid (HA) polymer as a targeting molecule, was synthesized for PTT. The fabricated AuNC@SiO2@HA nanocomposites underwent various in vitro studies to characterize their physicochemical properties, light absorption spectra, photothermal conversion ability, cellular uptake ability, and bioactivities. The synergistic effect of AuNC@SiO2@HA-mediated PTT and anti-PD-1 immunotherapy was evaluated using a mouse model of immune “cold” melanoma. The tumor-infiltrating T cells were assessed by immunofluorescence staining and flow cytometry. Furthermore, the mechanism of AuNC@SiO2@HA-induced T-cell infiltration was investigated through immunochemistry staining of the ICD-related markers, including HSP70, CRT, and HMGB1. Finally, the safety of AuNC@SiO2@HA nanocomposites was evaluated in vivo.ResultsThe AuNC@SiO2@HA nanocomposite with absorption covering 1064 nm was successfully synthesized. The nano-system can be effectively delivered into tumor cells, transform the optical energy into thermal energy upon laser irradiation, and induce tumor cell apoptosis in vitro. In an in vivo mouse melanoma model, AuNC@SiO2@HA nanocomposites significantly induced ICD and T-cell infiltration. The combination of AuNC@SiO2@HA and anti-PD-1 antibody synergistically inhibited tumor growth via stimulating robust T lymphocyte immune responses.DiscussionThe combination of AuNC@SiO2@HA-mediated PTT and anti-PD-1 immunotherapy proposed a neoteric strategy for oncotherapy, which efficiently convert the immune “cold” tumors into “hot” ones.

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Adaptive meets innate: CD8+ T cells kill MHC-I-negative tumour cells

Cited by 2 publications

References 1 publication

CD8+ T cells maintain killing of MHC-I-negative tumor cells through the NKG2D–NKG2DL axis

CD8+ T cells maintain killing of MHC-I-negative tumor cells through the NKG2D–NKG2DL axis

Photothermally sensitive gold nanocage augments the antitumor efficiency of immune checkpoint blockade in immune “cold” tumors

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