Strategies to overcome myeloid cell induced immune suppression in the tumor microenvironment

Cao, Jennifer H.; Chow, Lyndah; Dow, Steven

doi:10.3389/fonc.2023.1116016

Cited by 10 publications

(9 citation statements)

References 239 publications

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“…Lastly, wider dose-ranging studies might have been able to reveal greater differences in the anti-tumor activity of B7-H3-CXCR2 and B7-H3 CAR T cells. For future clinical studies, it is also worth exploring the addition of TME modifying drugs to deplete immune suppressive myeloid cell populations [ 70 ], thus converting it into an environment more favorable to T cells, as we have reported recently for osteosarcoma and glioma in dogs [ 54 , 71 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting osteosarcoma with canine B7-H3 CAR T cells and impact of CXCR2 Co-expression on functional activity

Cao,

Lake,

Impastato

et al. 2024

Cancer Immunol Immunother

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The use of large animal spontaneous models of solid cancers, such as dogs with osteosarcoma (OS), can help develop new cancer immunotherapy approaches, including chimeric antigen receptor (CAR) T cells. The goal of the present study was to generate canine CAR T cells targeting the B7-H3 (CD276) co-stimulatory molecule overexpressed by several solid cancers, including OS in both humans and dogs, and to assess their ability to recognize B7-H3 expressed by canine OS cell lines or by canine tumors in xenograft models. A second objective was to determine whether a novel dual CAR that expressed a chemokine receptor together with the B7-H3 CAR improved the activity of the canine CAR T cells. Therefore, in the studies reported here we examined B7-H3 expression by canine OS tumors, evaluated target engagement by canine B7-H3 CAR T cells in vitro, and compared the relative effectiveness of B7-H3 CAR T cells versus B7-H3-CXCR2 dual CAR T cells in canine xenograft models. We found that most canine OS tumors expressed B7-H3; whereas, levels were undetectable on normal dog tissues. Both B7-H3 CAR T cells demonstrated activation and OS-specific target killing in vitro, but there was significantly greater cytokine production by B7-H3-CXCR2 CAR T cells. In canine OS xenograft models, little anti-tumor activity was generated by B7-H3 CAR T cells; whereas, B7-H3-CXCR2 CAR T cells significantly inhibited tumor growth, inducing complete tumor elimination in most treated mice. These findings indicated therefore that addition of a chemokine receptor could significantly improve the anti-tumor activity of canine B7-H3 CAR T cells, and that evaluation of this new dual CAR construct in dogs with primary or metastatic OS is warranted since such studies could provide a critical and realistic validation of the chemokine receptor concept.

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Section: Discussionmentioning

confidence: 99%

Targeting osteosarcoma with canine B7-H3 CAR T cells and impact of CXCR2 Co-expression on functional activity

Cao,

Lake,

Impastato

et al. 2024

Cancer Immunol Immunother

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“…Rather than directly targeting effector cells, recent approaches aimed at manipulating immune-suppressive myeloid cells or their products have attracted attention as a strategy to restore patients' intrinsic antitumor immunity. Several of these are under clinical investigation, including compounds that inhibit arginase or indoleamine 2,3-dioxygenase (IDO) [ 25 , 26 ], and suppress TAM infiltration by blocking colony-stimulating factor 1 receptor (CSF-1R) [ 8 ]. Polarization of M2-TAMs into M1-TAMs is a second approach to stimulating antitumor immunity [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…Another approach by which to harness the antitumor activity of cytotoxic T lymphocytes (CTLs) is to ameliorate the immune-suppressive tumor microenvironment (TME) such as by decreasing the population of infiltrated myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and tumor-associated macrophages (TAMs). Strategies to deplete TAMs [ 8 ] or Tregs [ 9 ] are also being tested in the clinic. Thus, ways to reduce the numbers of these immune-suppressing cells from tumors are also attracting attention.…”

Section: Introductionmentioning

confidence: 99%

Blockade of EP4 by ASP7657 Modulates Myeloid Cell Differentiation In Vivo and Enhances the Antitumor Effect of Radiotherapy

Nishibata,

Amino,

Tanaka-Kado

et al. 2023

BioMed Research International

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The tumor microenvironment (TME) is thought to influence the antitumor efficacy of immuno-oncology agents through various products of both tumor and stromal cells. One immune-suppressive factor is prostaglandin E2 (PGE2), a lipid mediator whose biosynthesis is regulated by ubiquitously expressed cyclooxygenase- (COX-) 1 and inducible COX-2. By activating its receptors, PGE2 induces immune suppression to modulate differentiation of myeloid cells into myeloid-derived suppressor cells (MDSCs) rather than dendritic cells (DCs). Pharmacological blockade of prostaglandin E receptor 4 (EP4) causes a decrease in MDSCs, reprogramming of macrophage polarization, and increase in tumor-infiltrated T cells, leading to enhancement of antitumor immunity in preclinical models. Here, we report the effects of the highly potent EP4 antagonist ASP7657 on the DC population in tumor and antitumor immune activation in an immunocompetent mouse tumor model. Oral administration of ASP7657 inhibited tumor growth, which was accompanied by an increase in intratumor DC and CD8+ T cell populations and a decrease in the M-MDSC population in a CT26 immunocompetent mouse model. The antitumor activity of ASP7657 was dependent on CD8+ T cells and enhanced when combined with an antiprogrammed cell death-1 (PD-1) antibody. Notably, ASP7657 also significantly enhanced the antitumor efficacy of radiotherapy in an anti-PD-1 antibody refractory model. These results indicate that the therapeutic potential of ASP7657 arises via upregulation of DCs and subsequent CD8+ T cell activation in addition to suppression of MDSCs in mouse models and that combining EP4 antagonists with radiotherapy or an anti-PD-1 antibody can improve antitumor efficacy.

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“…[21][22][23] Myeloid cell targeting can become a key foundational approach to an overall strategy for improving tumor responses to immunotherapy. 24 Adjusting the MDSCs activity in cancer and other immune disorders/diseases without unduly comprising any normal physiological function can be done with AFP or AFP with AFP-binding drugs.…”

Section: Figure 1 Yanus Statue With Two Faces (Wikipedia)mentioning

confidence: 99%

Alpha-Fetoprotein: A Revolutionary Anti-Cancer Drug

Pak¹

2023

MRAJ

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Alpha-fetoprotein is an oncofetal protein the embryo produces during fetal development. The protein serves two critical functions simultaneously: it delivers nutrients to growing embryo cells and immature myeloid-derived suppressor cells, so the mother’s immune system doesn’t attack the embryo. The protein is present in minuscule amounts in adults and elevated alpha-fetoprotein levels serve as pregnancy or tumor markers. Exogenous alpha-fetoprotein has a new application as an immunotherapy drug. It can deliver drugs in a natural shuttle manner to myeloid-derived suppressor cells and stimulate them to calm the hyperactive immune response during many physiological and pathological conditions. On the other hand, alpha-fetoprotein loaded with toxins kills myeloid-derived suppressor cells and unleashes natural killer cells and cytotoxic lymphocytes to erase cancer. Most cancers have cells that specifically bind alpha-fetoprotein, and this protein targets chemotherapy to them also. So, alpha-fetoprotein with toxins combines both potent cancer immunotherapy and targeted chemotherapy activities. Alpha-fetoprotein can be chemically conjugated with or bind toxins non-covalently. Both preparations have demonstrated superior efficacy and safety compared to chemotherapy alone. Alpha-fetoprotein-toxin immuno/chemotherapy is not personalized. There is no need to preselect patients for cancer treatments as they have elevated myeloid-derived suppressor cell levels. The anti-cancer efficacy of porcine alpha-fetoprotein non-covalent complexes with selected toxins administered orally is a remarkable discovery that needs research. Cancer treatment and prevention are different issues, and they could need different approaches. Alpha-fetoprotein administration with drugs or toxins could be as effective in early cancer and metastasis prevention as mifepristone pills in pregnancy prevention.

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Strategies to overcome myeloid cell induced immune suppression in the tumor microenvironment

Cited by 10 publications

References 239 publications

Targeting osteosarcoma with canine B7-H3 CAR T cells and impact of CXCR2 Co-expression on functional activity

Targeting osteosarcoma with canine B7-H3 CAR T cells and impact of CXCR2 Co-expression on functional activity

Blockade of EP4 by ASP7657 Modulates Myeloid Cell Differentiation In Vivo and Enhances the Antitumor Effect of Radiotherapy

Alpha-Fetoprotein: A Revolutionary Anti-Cancer Drug

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