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Review
. 2023 Nov 24:14:1275904.
doi: 10.3389/fimmu.2023.1275904. eCollection 2023.

Potentiation of natural killer cells to overcome cancer resistance to NK cell-based therapy and to enhance antibody-based immunotherapy

Massimo Fantini  1 , Philip Martin Arlen  1 , Kwong Yok Tsang  1
Affiliations
Review

Potentiation of natural killer cells to overcome cancer resistance to NK cell-based therapy and to enhance antibody-based immunotherapy

Massimo Fantini et al. Front Immunol. .

Abstract

Natural killer (NK) cells are cellular components of the innate immune system that can recognize and suppress the proliferation of cancer cells. NK cells can eliminate cancer cells through direct lysis, by secreting perforin and granzymes, or through antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC involves the binding of the Fc gamma receptor IIIa (CD16), present on NK cells, to the constant region of an antibody already bound to cancer cells. Cancer cells use several mechanisms to evade antitumor activity of NK cells, including the accumulation of inhibitory cytokines, recruitment and expansion of immune suppressor cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), modulation of ligands for NK cells receptors. Several strategies have been developed to enhance the antitumor activity of NK cells with the goal of overcoming cancer cells resistance to NK cells. The three main strategies to engineer and boost NK cells cytotoxicity include boosting NK cells with modulatory cytokines, adoptive NK cell therapy, and the employment of engineered NK cells to enhance antibody-based immunotherapy. Although the first two strategies improved the efficacy of NK cell-based therapy, there are still some limitations, including immune-related adverse events, induction of immune-suppressive cells and further cancer resistance to NK cell killing. One strategy to overcome these issues is the combination of monoclonal antibodies (mAbs) that mediate ADCC and engineered NK cells with potentiated anti-cancer activity. The advantage of using mAbs with ADCC activity is that they can activate NK cells, but also favor the accumulation of immune effector cells to the tumor microenvironment (TME). Several clinical trials reported that combining engineered NK cells with mAbs with ADCC activity can result in a superior clinical response compared to mAbs alone. Next generation of clinical trials, employing engineered NK cells with mAbs with higher affinity for CD16 expressed on NK cells, will provide more effective and higher-quality treatments to cancer patients.

Keywords: ADCC; CAR-NK; NK cells; adoptive NK cell therapy; modulatory cytokines; monoclonal antibody.

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Conflict of interest statement

MF, KT and PA are employees of Precision Biologics, Inc. PA has an ownership interest in Precision Biologics, Inc. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Role of NK cells in immunoediting and mechanisms of immune-escape by cancer cells in the TME. During the elimination phase, NK cells can recognize and suppress cancer cells growth through different mechanisms. After the binding with their ligands, NK cells can kill cancer cells through direct lysis mediated by granzyme and perforin (A), through ADCC (B) or through apoptosis mediated by TRAIL and FasL and induced by the release of cytokines (TNF-α) (C). Cancer cells in the TME have developed different strategies to inhibit NK cells antitumor activity. One of these is promotion of recruitment and expansion of Tregs and MDSCs. MDSCs and Tregs can induce NK cells exhaustion and impairment by suppressing INF-γ production, and by inhibiting NKG2D pathway. Furthermore, cancer cells can release TGF-β or IL-6 in the TME to activate cancer-associated fibroblasts (CAFs), that in turn can contribute to the suppression of NK cells cytotoxicity and cytokine production. Other mechanisms include the release of immune suppressive cytokines and of ROS within the TME. Cancer cells can also increase the expression of CEACAM-1 or CEACAM-5 on their surface. These molecules bind to CEACAM-1 expressed on NK cells and this binding can lead to the suppression of NK cells cytotoxicity. Cancer cells can also suppress the NK-mediated ADCC through the proteolytic activity of the enzyme ADAM17. ADAM17 mediates the cleavage of CD16 on NK cells, which in turn suppresses NK cells antitumor activity through ADCC. The immunosuppressive activity of cancer cells towards NK cells is also exerted through the secretion of soluble factors in the bloodstream, such as soluble MICA. Elevated serum levels of soluble MICA suppress NK cell cytotoxicity by affecting the NKG2D pathway. Figure created with BioRender.com.
Figure 2
Figure 2
Strategies to potentiate the antitumor activity of NK cells to overcome the tumor resistance at the level of the TME. Cancer cells in the TME have developed several mechanisms to inhibit NK cells antitumor activity. Strategies used to potentiate the antitumor activity of NK cells to overcome the tumor resistance at the level of the TME include boosting NK cells with modulatory cytokines and adoptive NK cell therapy. (A) Cytokines, such as IL-2, IL-15, IL-12, IL-18, IL-21 can enhance the anti-cancer activity of NK cells through different mechanisms. NK cells antitumor activity can be also enhanced through the adoptive cell therapy, which consists of isolating NK cells from cellular components of immune system of a subject, engineering them ex vivo, expanding their numbers and then re-infuse them in a cancer patient. Sources of NK cells that can be used in adoptive therapy include autologous NK cells, allogeneic NK cells, and CAR-NK cells. (B) Adoptive NK cell therapy using autologous NK cells. NK cells are isolated from a cancer patient, expanded, and then re-infused in the same cancer patient. (C) Adoptive NK cell therapy using allogeneic NK cells. NK cells are isolated from a donor, expanded, and then re-infused in any recipient. The main sources for allogeneic NK cells are NK cells from peripheral blood, from umbilical cord blood, from human embryonic stem cells, from induced pluripotent stem cells and NK cell lines. (D) Adoptive NK cell therapy using engineered CAR-NK cells. CAR-NK cells can target and eliminate cancer cells with additional mechanisms beyond the CAR pathway, including ADCC. Figure created with BioRender.com.
Figure 3
Figure 3
Strategies to enhance FDA approved mAbs-mediated ADCC using engineered NK cells as effectors. mAbs able to mediate ADCC can activate NK cells, but also stimulate the accumulation of immune effector cells to the tumor site. Engineered NK cells have been found to enhance ADCC activity of several FDA approved mAbs. Sources of engineered NK cells as effectors include (A) Immunoligands; (B) Expanded autologous or allogeneic NK cells, NK cell lines with high affinity CD16, genetically modified NK cells. Figure created with BioRender.com.
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The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by Precision Biologics, Inc. The funder had no role in the design of the study, in the collection, analyses or interpretation of the data, in the writing of the manuscript or in the decision to publish the results.

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