Advancing natural killer therapies against cancer
2022; Cell Press; Volume: 185; Issue: 9 Linguagem: Inglês
10.1016/j.cell.2022.04.006
ISSN1097-4172
AutoresÉmilie Narni-Mancinelli, Éric Vivier,
Tópico(s)Virus-based gene therapy research
ResumoNatural killer (NK)-based therapies against cancer are emerging, but the understanding of NK cell functions needs to be completed to optimize these treatments. In this issue, Pan et al. (2022) show that pro-apoptotic molecules, such as BH3-mimetics, synergize with NK cells to induce mitochondria-driven apoptosis in tumor cells, thereby enhancing the efficacy of NK cell therapies. Natural killer (NK)-based therapies against cancer are emerging, but the understanding of NK cell functions needs to be completed to optimize these treatments. In this issue, Pan et al. (2022) show that pro-apoptotic molecules, such as BH3-mimetics, synergize with NK cells to induce mitochondria-driven apoptosis in tumor cells, thereby enhancing the efficacy of NK cell therapies. Cancer is a major health problem, and cancer therapies have been intensively investigated over decades. Patients can benefit from surgery, radiotherapy, and systemic chemotherapy depending on cancer indication. Surgery, when possible, remains the most effective treatment of localized primary tumors and associated regional lymphatics. Advanced cancers require systemic cytotoxic chemotherapy. However, the side effects of these treatments limit their application and efficacy. Cancer patients can also benefit from targeted therapies, such as monoclonal antibodies (mAbs) or small molecules, which can either deplete tumor cells or target the tumor cell growth signal cascade. Immuno-oncology is revolutionizing the treatment of cancers. Recent advances have focused on generating or unleashing tumor antigen-specific cytotoxic T cell responses. However, resistance to treatment and toxicity are often reported. Thus, despite major advances in these therapies, several cancer conditions remain true unmet medical needs and prompt the generation of a second wave of immune-oncology treatments (Demaria et al., 2019Demaria O. Cornen S. Daeron M. Morel Y. Medzhitov R. Vivier E. Harnessing innate immunity in cancer therapy.Nature. 2019; 574: 45-56https://doi.org/10.1038/s41586-019-1593-5Crossref PubMed Scopus (394) Google Scholar). Along this line, bringing natural killer (NK) cells to the clinic is very promising for a variety of reasons. NK cells can recognize a wide array of tumor cells across all cancer types and contribute to their elimination by direct cytotoxicity and by shaping a multicellular protective immune response via their secretion of cytokines and chemokines (Demaria et al., 2019Demaria O. Cornen S. Daeron M. Morel Y. Medzhitov R. Vivier E. Harnessing innate immunity in cancer therapy.Nature. 2019; 574: 45-56https://doi.org/10.1038/s41586-019-1593-5Crossref PubMed Scopus (394) Google Scholar; Myers and Miller, 2021Myers J.A. Miller J.S. Exploring the NK cell platform for cancer immunotherapy.Nat. Rev. Clin. Oncol. 2021; 18: 85-100https://doi.org/10.1038/s41571-020-0426-7Crossref PubMed Scopus (389) Google Scholar). The presence of functional NK cells correlates with better overall survival in several blood and solid cancers. Therefore, harnessing NK cells to fight cancer is being evaluated in clinic using mAbs or cell therapies. Importantly, NK-cell treatments appear safer than T cell treatments (Daher and Rezvani, 2021Daher M. Rezvani K. Outlook for New CAR-based therapies with a Focus on CAR NK cells: what Lies beyond CAR-Engineered T cells in the Race against cancer.Cancer Discov. 2021; 11: 45-58https://doi.org/10.1158/2159-8290.cd-20-0556Crossref PubMed Scopus (0) Google Scholar). In this issue of Cell, Pan and colleagues sought to improve antitumor NK cell activity by making tumor cells more sensitive to NK-cell-induced death (Pan et al., 2022Pan R. Ryan J. Pan D. Wucherpfennig K.W. Letai A. Augmenting NK cell-based immunotherapy by targeting 1 mitochondrial apoptosis.Cell. 2022; 185: 1521-1538Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). There are several forms of cell death: apoptosis, necrosis, pyroptosis, and ferroptosis. It has been known for years that NK cells induce the apoptosis of tumor cells. Two pathways can trigger apoptosis: the extrinsic pathway induced by engagement of the death receptors such as TRAIL and Fas, and the intrinsic pathway involving the mitochondria. Pan et al. discovered that the NK-cell-mediated killing mechanism requires the mitochondrial-mediated apoptosis pathway within the tumor cell (Pan et al., 2022Pan R. Ryan J. Pan D. Wucherpfennig K.W. Letai A. Augmenting NK cell-based immunotherapy by targeting 1 mitochondrial apoptosis.Cell. 2022; 185: 1521-1538Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). This mechanism occurs at a low effector:target ratio, a condition that is likely found in patients where NK cells are outnumbered by cancer cells. Apoptosis via mitochondria is regulated by the pro- and anti-apoptotic proteins of the BCL-2 family. Anti-apoptotic proteins (BCL-2, BCL-w, MCL-1, BFL-1, and BCL-XL) prevent apoptosis by binding and sequestering their pro-apoptotic counterparts (PUMA, BIM, BID, BAD, BIK, NOXA, and BMF) (Singh et al., 2019Singh R. Letai A. Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins.Nat. Rev. Mol. Cell Biol. 2019; 20: 175-193https://doi.org/10.1038/s41580-018-0089-8Crossref PubMed Scopus (910) Google Scholar). A subset of BH3 (BCL-2 homology domain 3)-only proteins, including BIM and BID, activate the effectors of apoptosis (BAX and BAK), which lead to mitochondrial outer membrane permeabilization (MOMP). MOMP is recognized as the point of no return in programmed cell death and causes the release of cytochrome c into the cytosol, resulting in the formation of the apoptosome and, ultimately, activating the caspase cascade (caspases 9/7/3). A cell that expresses just enough pro-survival proteins to contain pro-apoptotic signals is considered “primed” for apoptosis. Consistent with the importance of mitochondrial apoptosis in the regulation of NK cell-mediated killing of tumor cells, Pan and coworkers showed in their model that the silencing of the NK cell cytolytic molecule granzyme B impaired NK-cell-mediated tumor cell killing. Granzyme B has indeed been reported to induce mitochondrial apoptosis through the activation of BID (Lord et al., 2003Lord S.J. Rajotte R.V. Korbutt G.S. Bleackley R.C. Granzyme B: a natural born killer.Immunol. Rev. 2003; 193: 31-38https://doi.org/10.1034/j.1600-065x.2003.00044.xCrossref PubMed Scopus (0) Google Scholar). However, the contribution of NK cell cytokines, such as IFN-γ, in the induction of mitochondrial apoptosis in cancer cells remains to be analyzed. In the search of novel antitumor therapies, efforts have been made to identify cytotoxic molecules that directly act on BCL-2 protein family, such as the BH3 mimetics (Singh et al., 2019Singh R. Letai A. Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins.Nat. Rev. Mol. Cell Biol. 2019; 20: 175-193https://doi.org/10.1038/s41580-018-0089-8Crossref PubMed Scopus (910) Google Scholar). These are small molecules that disrupt the interaction of the BH3 domain pro-apoptotic molecules with BCL-2 proteins, thus limiting cell survival. The authors showed that NK cell treatment combined with low doses of BH3 mimetics synergizes to reach the threshold for apoptosis and cause cell death. The dependence on specific pro-survival BCL-2 family proteins is specific to each type of tumor cell and can be determined via a BH3 profiling assay. Of note, BH3 mimetics sensitize tumor cells for NK-cell-mediated killing but do not promote the expression of activating ligands, such as the NKG2D ligand MICA/B. The induction of other ligands for other activating receptors remain to be evaluated. Importantly, NK cell pre-activation with interleukin-2 (IL-2) makes them less sensitive to BH3 mimetics, further supporting their combination for effective antitumor treatment. In xenograft mouse models of blood and solid cancers, BH3 mimetics administration in combination with the transfer of activated NK cells significantly improve tumor cell control and mouse survival. Several studies have reported that increases in the numbers of intratumoral and circulating NK cells are associated with favorable outcomes of treatment with anti-EGFR mAb (cetuximab) and anti-CD20 mAb (obinutuzumab and rituximab) (Myers and Miller, 2021Myers J.A. Miller J.S. Exploring the NK cell platform for cancer immunotherapy.Nat. Rev. Clin. Oncol. 2021; 18: 85-100https://doi.org/10.1038/s41571-020-0426-7Crossref PubMed Scopus (389) Google Scholar). Indeed, a cell that is dependent on EGFR will upregulate pro-apoptotic BIM when EGFR signaling is inhibited, thus lowering the threshold for apoptosis (Deng et al., 2007Deng J. Shimamura T. Perera S. Carlson N.E. Cai D. Shapiro G.I. Wong K.K. Letai A. Proapoptotic BH3-only BCL-2 family protein BIM connects death signaling from epidermal growth factor receptor inhibition to the mitochondrion.Cancer Res. 2007; 67: 11867-11875https://doi.org/10.1158/0008-5472.can-07-1961Crossref PubMed Scopus (0) Google Scholar). Pan and coworkers showed in their report that rituximab also pushes cells toward apoptosis (Pan et al., 2022Pan R. Ryan J. Pan D. Wucherpfennig K.W. Letai A. Augmenting NK cell-based immunotherapy by targeting 1 mitochondrial apoptosis.Cell. 2022; 185: 1521-1538Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). Therefore, NK-cell-mediated killing of primed tumor cells may be involved in the underlying mechanism of anti-EGFR-mAb and anti-CD20-mAb therapies. The findings of Pan et al. could be applied in a combinatorial way to improve NK-cell-based immunotherapies (Figure 1), for example, by combining BH3 mimetics with recent therapies that aim at unleashing NK cells with immune checkpoint inhibitors, such as anti-NKG2A (monalizumab), anti-TIGIT (tiragolumab and ociperlimab), and anti-LAG3 (relatlimab) mAbs (Demaria et al., 2019Demaria O. Cornen S. Daeron M. Morel Y. Medzhitov R. Vivier E. Harnessing innate immunity in cancer therapy.Nature. 2019; 574: 45-56https://doi.org/10.1038/s41586-019-1593-5Crossref PubMed Scopus (394) Google Scholar). Alternatively, BH3 mimetics could be combined with recent therapeutics designed to promote NK cell activity via NK cell engagers, which bind NK cell activating receptors (CD16 and/or natural cytotoxic receptor) and a tumor antigen (Demaria et al., 2021Demaria O. Gauthier L. Debroas G. Vivier E. Natural killer cell engagers in cancer immunotherapy: Next generation of immuno-oncology treatments.Eur. J. Immunol. 2021; 51: 1934-1942https://doi.org/10.1002/eji.202048953Crossref PubMed Scopus (55) Google Scholar). The benefit of combining these therapies remains to be tested. Harnessing the potential of apoptosis as a strategic approach to kill cancer cells is not new. Many common types of anti-cancer therapies, such as chemotherapy and radiotherapy, engage the mitochondrial apoptosis pathway (Singh et al., 2019Singh R. Letai A. Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins.Nat. Rev. Mol. Cell Biol. 2019; 20: 175-193https://doi.org/10.1038/s41580-018-0089-8Crossref PubMed Scopus (910) Google Scholar). The approval of the BH3 mimetic BCL-2 selective inhibitor venetoclax in several malignant therapies is a milestone in targeting the apoptotic pathway for cancer treatment. Venetoclax provides an additive effect to the anti-CD38 mAb daratumumab for NK-cell-mediated killing of multiple myeloma cell lines (Nakamura et al., 2021Nakamura A. Suzuki S. Kanasugi J. Ejiri M. Hanamura I. Ueda R. Seto M. Takami A. Synergistic effects of venetoclax and Daratumumab on antibody-dependent cell-mediated natural killer cytotoxicity in multiple myeloma.Int. J. Mol. Sci. 2021; 22: 10761https://doi.org/10.3390/ijms221910761Crossref PubMed Scopus (6) Google Scholar). In general, cancer cells that are sensitive to these drugs are more prone to apoptosis priming than their non-transformed counterparts, thus creating a therapeutic window for tumor response to pro-apoptotic therapy (Singh et al., 2019Singh R. Letai A. Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins.Nat. Rev. Mol. Cell Biol. 2019; 20: 175-193https://doi.org/10.1038/s41580-018-0089-8Crossref PubMed Scopus (910) Google Scholar). However, toxicity of these pro-apoptotic agents is a burning matter limiting their efficacy. This issue could be circumvented by reducing the dose of these treatments and combining them to NK cell therapies, so that the level of apoptotic stress induced within a cancer cell is insufficient to trigger apoptosis but enough to lower the threshold for apoptosis, thereby sensitizing tumor cells for an efficient NK-cell-mediated killing. The E.V. laboratory at CIML and Assistance-Publique des Hôpitaux de Marseille is supported by funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (TILC, grant agreement no. 694502, grant agreement no. 875102 - MInfla-Tilc), the Agence Nationale de la Recherche, including the PIONEER Project (ANR-17-RHUS-0007), MSDAvenir, Innate Pharma, and institutional grants to the CIML (INSERM, CNRS, and Aix-Marseille University) and Marseille Immunopole. E.V. is an employee of Innate Pharma. Augmenting NK cell-based immunotherapy by targeting mitochondrial apoptosisPan et al.CellApril 20, 2022In BriefNK cells are an attractive option for cell-based therapy but require optimization. BH3 mimetics chosen by BH3 profiling synergized with NK cell therapy to enhance cancer-cell killing by NK cells in an approach that could also be used for other cell therapy platforms. Full-Text PDF Open Archive
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