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Review
. 2022 Oct 6:13:999549.
doi: 10.3389/fimmu.2022.999549. eCollection 2022.

Target tumor microenvironment by innate T cells (VSports app下载)

Yan-Ruide Li  1 , Matthew Wilson  1 , Lili Yang  1   2   3   4
Affiliations
Review

Target tumor microenvironment by innate T cells

Yan-Ruide Li (VSports手机版) et al. Front Immunol. .

Abstract

The immunosuppressive tumor microenvironment (TME) remains one of the most prevailing barriers obstructing the implementation of effective immunotherapy against solid-state cancers. Eminently composed of immunosuppressive tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) among others, the TME attenuates the effects of immune checkpoint blockade and adoptive cell therapies, mandating a novel therapy capable of TME remediation. In this review we explore the potential of three innate-like T cell subsets, invariant natural killer T (iNKT), mucosal-associated invariant T (MAIT) cells, and gamma delta T (γδT) cells, that display an intrinsic anti-TAM/MDSC capacity. Exhibiting both innate and adaptive properties, innate-like T cell types express a subset-specific TCR with distinct recombination, morphology, and target cell recognition, further supplemented by a variety of NK activating receptors. Both NK activating receptor and TCR activation result in effector cell cytotoxicity against targeted immunosuppressive cells for TME remediation. In addition, innate-like T cells showcase moderate levels of tumor cell killing, providing dual antitumor and anti-TAM/MDSC function. This latent antitumor capacity can be further bolstered by chimeric antigen receptor (CAR) engineering for recognition of tumor specific antigens to enhance antitumor targeting. In contrast with established CAR-T cell therapies, adoption of these innate-like cell types provides an enhanced safety profile without the risk of graft versus host disease (GvHD), due to their non-recognition of mismatched major histocompatibility complex (MHC) molecules, for use as widely accessible, allogeneic "off-the-shelf" cancer immunotherapy VSports手机版. .

Keywords: cell-based immunotherapy; gamma delta T (γδT) cell; innate T cell; invariant natural killer T (iNKT) cell; mucosal-associated invariant T (MAIT) cell; myeloid-derived suppressor cell (MDSC); tumor microenvironment (TME); tumor-associated macrophage (TAM) V体育安卓版. .

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Conflict of interest statement

Y-RL and LY are inventors on patents relating to this article filed by UCLA. LY is a scientific advisor to AlzChem and Amberstone Biosciences, and a co-founder, stockholder, and advisory board member of Appia Bio. None of the declared companies contributed to or directed any of the research reported in this article V体育ios版. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

V体育ios版 - Figures

Figure 1
Figure 1
Cell-based therapy to target immunosuppressive cells in solid tumor microenvironment (TME). (A) The TME is composed of a heterogeneous milieu of tumor and immune cells. Various immunosuppressive cells such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs) and T regulatory cells, suppress or reprogram the antitumor immune response. (B) Different chimeric antigen receptors (CARs) were utilized to generate CAR-T cells, including fibroblast activation protein (FAP) CAR, Folate receptor β (FRβ) CAR, CD123 CAR and C-C motif chemokine receptor 4 (CCR4) CAR. (C) Innate T cells, including invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, and gamma delta T (γδT) cells, efficiently target immunosuppressive cells, and these innate T cells could be further engineered with CARs and achieve both tumor cell and immunosuppressive cell elimination.
Figure 2
Figure 2
Targeting tumor and immunosuppressive cells by innate T cells. (A) Diagram showing iNKT cells target CD1d+ tumor cells using NK/TCR double mechanisms. MIC, MHC class I chain-related protein. ULBP, UL16 binding protein. (B) Diagram showing iNKT cells target CD1d+ TAMs using NK/TCR double mechanisms. (C) Diagram showing MAIT cells target CD1d+ TAMs using NK/TCR double mechanisms. MR1, major histocompatibility complex, class I-related protein. 5-OP-RU, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil. 5-OP-RU is a microbial riboflavin-derived antigen and can specifically activate MAIT cells. (D) Diagram showing γδT cells target CD1d+ TAMs using NK/TCR double mechanisms. Zoledronate is a nitrogen-containing bisphosphonate and can activate γδT cells.
Figure 3
Figure 3
Two approaches to generate CAR-engineered innate T cells. (A) Innate T cells are enriched from healthy donor peripheral blood mononuclear cells (PBMCs) via cell sorting, cultured in vitro and engineered with CARs. The generated CAR-engineered innate T cells could target both tumor and immunosuppressive cells. However, these cells have limited expansion fold and yield; therefore, the cell products could be adoptively transferred to less cancer patients. (B) Stem cells such as hematopoietic stem cells (HSCs) and pluripotent stem cells (PSCs; include embryonic stem cells and induced PSCs) could be engineered with innate T cell TCR and then cultured in the in vitro differentiation systems where the stem cells develop into mature innate T cells. The platforms could be easily combined with CAR engineering and other genetic modifications such as CRISPR-Cas9. The stem cell-derived innate T cells have high yield and purity and can be transferred to more cancer patients.
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