- Email: [email protected]
Born to Kill: NK Cells Go to War against Cancer
TRECAN 326 No. of Pages 3
Spotlight
Born to Kill: NK Cells Go to War against Cancer Erik Wennerberg1,* and Lorenzo Galluzzi1,2,3,* Preclinical and clinical data emerging over the past year demonstrate that cancer cells suppress the cytotoxic functions of natural killer cells by a variety of mechanisms. These findings reveal a new arsenal of actionable therapeutic targets to drive clinically relevant immune responses against cancer. Natural killer (NK) cells are a group of innate lymphoid cells widely known for their ability to mediate robust cytotoxic functions in the context of viral infection. Data accumulating over the past decade demonstrated that NK cells also play a major role in the control of metastatic cancer dissemination [1]. However, NK cells have long been considered of limited relevance for the natural and therapydriven surveillance of primary human tumors, two clinically relevant processes that were largely attributed to CD8+ cytotoxic T cells (CTLs) [2]. Recent findings from multiple independent groups identify various molecular mechanisms whereby malignant cells keep NK cells under check [3–6]. All these mechanisms offer novel therapeutic targets that (at least potentially) can be harnessed to unleash the cytotoxic activity of NK cells against cancer. Contrary to CD8+ CTLs, which employ their T cell receptor (TCR) to recognize a specific antigen presented in the context of MHC class I molecules, NK cells operate in an antigen-independent manner, with their cytotoxic activity being
regulated by a compound input from germline-encoded stimulatory and inhibitory receptors [1]. One of the best-characterized NK cell-activating receptors (NKARs) is killer cell lectin-like receptor K1 (KLRK1, best known as NKG2D). NKG2D responds to multiple NK cell-activating ligands (NKALs) that are upregulated on the surface of infected or otherwise stressed cells, including MHC class I polypeptide-related sequence A (MICA) and MICB [1]. Cancer cells elude NKG2D signaling through the proteolytic shedding of NKALs, resulting in the formation of soluble fragments that operate as decoys for NKARs [7]. Recently, Ferrari de Andrade and collaborators (from Dana-Farber Cancer Institute, Cambridge, MA) rationally designed antibodies specific for the MICA a3 domain (the major site of proteolytic shedding by metalloproteinases) [6]. MICA a3-specific antibodies not only inhibited both MICA and MICB shedding by cancer cells but also mediated robust therapeutic effects, both in fully immunocompetent mouse tumor models and in immunocompromised mice reconstituted with human NK cells and challenged with human melanoma cells [6]. Although to the best of our knowledge this strategy has not yet entered clinical development, the findings of Ferrari de Andrade et al. delineate a novel, potentially actionable therapeutic target to counteract NK cell immunosuppression in cancer. NK cells are strongly suppressed in their cytotoxic functions by a class of receptors commonly known as killer cell immunoglobulin-like receptor (KIRs), which recognize canonical MHC class I molecules [namely, human leukocyte antigen (HLA)-A, HLA-B, and HLA-C] [1]. Over the past decade, considerable efforts have been devoted to the development of KIR-targeting monoclonal antibodies against cancer, with promising preclinical and clinical findings [8]. However, the
clinical development of lirilumab, a firstin-class pan-KIR antibody, appears to stand at an impasse (www.clinicaltrials. gov), potentially reflecting the limited engagement of KIRs in the tumor microenvironment. At odds with its canonical counterparts, the non-canonical MHC class I molecule HLA-E suppresses the activity of NK cells upon binding to a heterodimeric receptor composed of KLRC1 (best known as NKG2A) and KLRD1 (best known as CD94) [1]. Very recent data from André and colleagues (from Innate Pharma, Marseille, France) and van Montfoort and collaborators (from Leiden University Medical Center, Leiden, The Netherlands) demonstrate that NKG2A signaling plays a key role in the suppression of NK cell activity by malignant cells [3,4]. Consistent with this notion, targeting the HLA-E ! NKG2A signaling axis with monoclonal antibodies or genetic interventions boosted the efficacy of therapeutic cancer vaccines in four different mouse tumor models [4]. Moreover, combined inhibition of NKG2A and programmed cell death 1 (PDCD1, a co-inhibitory receptor best known as PD1) signaling, with antibodies specific for either PD-1 or its ligand (CD274, best known as PD-L1), mediated superior therapeutic effects compared to either treatment alone in immunocompetent mice grafted with two different mouse lymphoma cell lines [3]. Importantly, Andr é and collaborators also reported preliminary data from a Phase II clinical trial testing monalizumab (a monoclonal antibody specific for human NKG2A) in combination with cetuximab (which targets the epidermal growth factor receptor) in patients with squamous cell carcinoma of the head and neck (SCCHN), based on a dual rationale: (i) human SCCHN expresses high levels of HLA-E [3]; and (ii) although originally designed as a targeted anticancer agent, cetuximab also enables antibody-dependent cellular toxicity by NK cells [9]. Objective response
Trends in Cancer, Month Year, Vol. xx, No. yy
1
TRECAN 326 No. of Pages 3
rate to monalizumab plus cetuximab was 31% in the absence of major adverse events [3]. Altogether, these findings demonstrate that NKG2A is engaged in the microenvironment of (at least some) tumors, de facto constituting an actionable therapeutic target.
GZMB
IFNγ
PRF1
NK cell
GZMB
PRF1
Cancer cell
IFNγ
CTL
NKG2D NKAL
TCR
NKG2A
1
PD-1 PD-L1
2
The adoptive transfer of NK cells has also been investigated as a potential strategy KIR for some oncological indications, so far 3 HLA-E with mediocre results (especially for solid CCL5 malignancies) [10]. It is tempting to specMMPs XCL1 4 ulate, but remains to be formally eluciFLT3LG sNKALs dated, that the efficient shedding of NKALs by cancer cells and the engageDC ment of NKG2A on tumor-infiltrating NK HLA-A Acvaon IL-12 cells may account, at least in part, for this therapeutic defeat. Of note, additional Recruitment and acvaon Cross-priming receptors have been shown to suppress the cytotoxic activity of NK cells against malignant and virally infected cells, includ- Figure 1. NK Cells in Anticancer Immunity. Both natural killer (NK) cells and CD8+ cytotoxic T lymphocytes ing single Ig and TIR domain containing (CTLs) can mediate direct anticancer effects by secreting cytotoxic molecules such as granzyme B (GZMB), perforin 1 (PRF1), and interferon gamma (IFNg). Moreover, NK cells can drive the recruitment of dendritic cells (SIGIRR, best known as IL-1R8) [5]. To (DCs) to the tumor microenvironment and their activation as they secrete XCL1, CCL5, and FLT3LG, which the best of our knowledge, however, no sets the stage for CTL-dependent anticancer immunity. Conversely, DCs can support the cytotoxic functions + molecules targeting SIGIRR are currently of NK cells by producing IL-12. However, malignant cells subvert the functions of both NK cells and CD8 CTLs via multiple mechanisms, including (1) the expression of HLA-E, which mediates immunosuppressive functions under clinical development (www. upon binding to NKG2A on the surface of NK cells and (less so) CD8+ CTLs; (2) the expression of PD-L1, a coclinicaltrials.gov). inhibitory molecule that signals upon binding to PD-1 on the surface of CD8+ CTLs and (less so) NK cells; (3) the Importantly, NKG2A, NKG2D, and PD-1 are expressed by both NK cells and CD8+ CTLs, although to different degrees [1,3]. Moreover, recent data elucidated several aspects of the interaction between NK cells and dendritic cells (DCs) in the elicitation of anticancer immune responses. On the one hand, intratumoral NK cells have been shown to recruit type I conventional DCs, which are key for the crosspriming of CD8+ CTL-dependent anticancer immunity, to the tumor microenvironment and activate them, owing to their ability to secrete X-C motif chemokine ligand 1 (XCL1), C-C motif chemokine ligand 5 (CCL5), and fms-related tyrosine kinase 3 ligand (FLT3LG) [11,12]. On the on other hand, type I conventional DCs have been demonstrated to support the cytotoxic activity of NK cells by producing interleukin 12 (IL-12) [13]. 2
Trends in Cancer, Month Year, Vol. xx, No. yy
expression of HLA-A, HLA-B, and HLA-C to finely tuned degrees, which render cancer cells invisible to CD8+ CTLs and/or inhibit NK cell activation upon binding to killer cell immunoglobulin-like receptors (KIRs); and (4) the expression of metalloproteinases (MMPs) that shed NK cell activatory ligands from the cancer cell surface, which results in the production of soluble NK cell-activating ligands (sNKALs) operating as molecular decoys. All these mechanisms constitute potentially actionable targets to relieve immunosuppression in the tumor microenvironment and hence unleash the antitumor functions of NK cells and CD8+ CTLs. Abbreviation: TCR, T cell receptor.
Taken together, these findings delineate a complex network of interactions between innate and adaptive immune cells that underlie anticancer immunity. NK cells occupy multiple key positions in such network, offering various targets for therapeutic interventions (Figure 1). Given the elevated degree of redundancy that characterizes the immunosuppressive pathways activated in the tumor microenvironment, we surmise that only combinatorial strategies simultaneously actioning multiple of these targets will exhibit superior clinical efficacy.
Additional preclinical and clinical studies are urgently required to define the best approach to fight cancer with the help of both T cells and NK cells. Acknowledgments E.W. is supported by Breakthrough Fellowship Award from the U. S. Department of Defense (DoD) (W81XWH-17-1-0029). L.G. is supported by a Breakthrough Level 2 grant from the DoD, Breast Cancer Research Program (BC180476P1); by a startup grant from the Department of Radiation Oncology at Weill Cornell Medicine (New York, USA); by industrial collaborations with Lytix (Oslo, Norway) and Phosplatin (New York, USA); and by donations from Phosplatin
TRECAN 326 No. of Pages 3
(New York, USA), the Luke Heller TECPR2 Foundation (Massachusetts, USA), and Sotio a.s. (Prague, Czech Republic).
Disclaimer Statement L.G. provides remunerated consulting to OmniSEQ (Buffalo, NY, USA), Astra Zeneca (Gaithersburg, MD, USA), VL47 (New York, NY, USA), and the Luke Heller TECPR2 Foundation (Boston, MA, USA), and he is member of the Scientific Advisory Committee of OmniSEQ. 1 Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA 2 Sandra and Edward Meyer Cancer Center, New York, NY, USA 3 Université Paris Descartes, Sorbonne Paris Cité, Paris,
France
https://doi.org/10.1016/j.trecan.2018.12.005 © 2019 Elsevier Inc. All rights reserved.
References 1. Lopez-Soto, A. et al. (2017) Control of metastasis by NK cells. Cancer Cell 32, 135–154 2. Galluzzi, L. et al. (2018) The hallmarks of successful anticancer immunotherapy. Sci. Transl. Med. 10, eaat7807 3. Andre, P. et al. (2018) Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell 175, 1731–1743.e13 4. van Montfoort, N. et al. (2018) NKG2A blockade potentiates CD8 T cell immunity induced by cancer vaccines. Cell 175, 1744–1755.e15 5. Molgora, M. et al. (2017) IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity. Nature 551, 110–114 6. Ferrari de Andrade, L. et al. (2018) Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity. Science 359, 1537–1542
7. Lopez-Soto, A. et al. (2017) Soluble NKG2D ligands limit the efficacy of immune checkpoint blockade. Oncoimmunology 6, e1346766 8. Kohrt, H.E. et al. (2014) Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies. Blood 123, 678–686 9. Galluzzi, L. et al. (2015) Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 28, 690–714 10. Fournier, C. et al. (2017) Trial Watch: adoptively transferred cells for anticancer immunotherapy. Oncoimmunology 6, e1363139 11. Bottcher, J.P. et al. (2018) NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037 e1014 12. Barry, K.C. et al. (2018) A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat. Med. 24, 1178–1191 13. Mittal, D. et al. (2017) Interleukin-12 from CD103(+) Batf3dependent dendritic cells required for NK-cell suppression of metastasis. Cancer Immunol. Res. 5, 1098–1108
*Correspondence: [email protected] (E. Wennerberg) and [email protected] (L. Galluzzi).
Trends in Cancer, Month Year, Vol. xx, No. yy
3
Spotlight
Born to Kill: NK Cells Go to War against Cancer Erik Wennerberg1,* and Lorenzo Galluzzi1,2,3,* Preclinical and clinical data emerging over the past year demonstrate that cancer cells suppress the cytotoxic functions of natural killer cells by a variety of mechanisms. These findings reveal a new arsenal of actionable therapeutic targets to drive clinically relevant immune responses against cancer. Natural killer (NK) cells are a group of innate lymphoid cells widely known for their ability to mediate robust cytotoxic functions in the context of viral infection. Data accumulating over the past decade demonstrated that NK cells also play a major role in the control of metastatic cancer dissemination [1]. However, NK cells have long been considered of limited relevance for the natural and therapydriven surveillance of primary human tumors, two clinically relevant processes that were largely attributed to CD8+ cytotoxic T cells (CTLs) [2]. Recent findings from multiple independent groups identify various molecular mechanisms whereby malignant cells keep NK cells under check [3–6]. All these mechanisms offer novel therapeutic targets that (at least potentially) can be harnessed to unleash the cytotoxic activity of NK cells against cancer. Contrary to CD8+ CTLs, which employ their T cell receptor (TCR) to recognize a specific antigen presented in the context of MHC class I molecules, NK cells operate in an antigen-independent manner, with their cytotoxic activity being
regulated by a compound input from germline-encoded stimulatory and inhibitory receptors [1]. One of the best-characterized NK cell-activating receptors (NKARs) is killer cell lectin-like receptor K1 (KLRK1, best known as NKG2D). NKG2D responds to multiple NK cell-activating ligands (NKALs) that are upregulated on the surface of infected or otherwise stressed cells, including MHC class I polypeptide-related sequence A (MICA) and MICB [1]. Cancer cells elude NKG2D signaling through the proteolytic shedding of NKALs, resulting in the formation of soluble fragments that operate as decoys for NKARs [7]. Recently, Ferrari de Andrade and collaborators (from Dana-Farber Cancer Institute, Cambridge, MA) rationally designed antibodies specific for the MICA a3 domain (the major site of proteolytic shedding by metalloproteinases) [6]. MICA a3-specific antibodies not only inhibited both MICA and MICB shedding by cancer cells but also mediated robust therapeutic effects, both in fully immunocompetent mouse tumor models and in immunocompromised mice reconstituted with human NK cells and challenged with human melanoma cells [6]. Although to the best of our knowledge this strategy has not yet entered clinical development, the findings of Ferrari de Andrade et al. delineate a novel, potentially actionable therapeutic target to counteract NK cell immunosuppression in cancer. NK cells are strongly suppressed in their cytotoxic functions by a class of receptors commonly known as killer cell immunoglobulin-like receptor (KIRs), which recognize canonical MHC class I molecules [namely, human leukocyte antigen (HLA)-A, HLA-B, and HLA-C] [1]. Over the past decade, considerable efforts have been devoted to the development of KIR-targeting monoclonal antibodies against cancer, with promising preclinical and clinical findings [8]. However, the
clinical development of lirilumab, a firstin-class pan-KIR antibody, appears to stand at an impasse (www.clinicaltrials. gov), potentially reflecting the limited engagement of KIRs in the tumor microenvironment. At odds with its canonical counterparts, the non-canonical MHC class I molecule HLA-E suppresses the activity of NK cells upon binding to a heterodimeric receptor composed of KLRC1 (best known as NKG2A) and KLRD1 (best known as CD94) [1]. Very recent data from André and colleagues (from Innate Pharma, Marseille, France) and van Montfoort and collaborators (from Leiden University Medical Center, Leiden, The Netherlands) demonstrate that NKG2A signaling plays a key role in the suppression of NK cell activity by malignant cells [3,4]. Consistent with this notion, targeting the HLA-E ! NKG2A signaling axis with monoclonal antibodies or genetic interventions boosted the efficacy of therapeutic cancer vaccines in four different mouse tumor models [4]. Moreover, combined inhibition of NKG2A and programmed cell death 1 (PDCD1, a co-inhibitory receptor best known as PD1) signaling, with antibodies specific for either PD-1 or its ligand (CD274, best known as PD-L1), mediated superior therapeutic effects compared to either treatment alone in immunocompetent mice grafted with two different mouse lymphoma cell lines [3]. Importantly, Andr é and collaborators also reported preliminary data from a Phase II clinical trial testing monalizumab (a monoclonal antibody specific for human NKG2A) in combination with cetuximab (which targets the epidermal growth factor receptor) in patients with squamous cell carcinoma of the head and neck (SCCHN), based on a dual rationale: (i) human SCCHN expresses high levels of HLA-E [3]; and (ii) although originally designed as a targeted anticancer agent, cetuximab also enables antibody-dependent cellular toxicity by NK cells [9]. Objective response
Trends in Cancer, Month Year, Vol. xx, No. yy
1
TRECAN 326 No. of Pages 3
rate to monalizumab plus cetuximab was 31% in the absence of major adverse events [3]. Altogether, these findings demonstrate that NKG2A is engaged in the microenvironment of (at least some) tumors, de facto constituting an actionable therapeutic target.
GZMB
IFNγ
PRF1
NK cell
GZMB
PRF1
Cancer cell
IFNγ
CTL
NKG2D NKAL
TCR
NKG2A
1
PD-1 PD-L1
2
The adoptive transfer of NK cells has also been investigated as a potential strategy KIR for some oncological indications, so far 3 HLA-E with mediocre results (especially for solid CCL5 malignancies) [10]. It is tempting to specMMPs XCL1 4 ulate, but remains to be formally eluciFLT3LG sNKALs dated, that the efficient shedding of NKALs by cancer cells and the engageDC ment of NKG2A on tumor-infiltrating NK HLA-A Acvaon IL-12 cells may account, at least in part, for this therapeutic defeat. Of note, additional Recruitment and acvaon Cross-priming receptors have been shown to suppress the cytotoxic activity of NK cells against malignant and virally infected cells, includ- Figure 1. NK Cells in Anticancer Immunity. Both natural killer (NK) cells and CD8+ cytotoxic T lymphocytes ing single Ig and TIR domain containing (CTLs) can mediate direct anticancer effects by secreting cytotoxic molecules such as granzyme B (GZMB), perforin 1 (PRF1), and interferon gamma (IFNg). Moreover, NK cells can drive the recruitment of dendritic cells (SIGIRR, best known as IL-1R8) [5]. To (DCs) to the tumor microenvironment and their activation as they secrete XCL1, CCL5, and FLT3LG, which the best of our knowledge, however, no sets the stage for CTL-dependent anticancer immunity. Conversely, DCs can support the cytotoxic functions + molecules targeting SIGIRR are currently of NK cells by producing IL-12. However, malignant cells subvert the functions of both NK cells and CD8 CTLs via multiple mechanisms, including (1) the expression of HLA-E, which mediates immunosuppressive functions under clinical development (www. upon binding to NKG2A on the surface of NK cells and (less so) CD8+ CTLs; (2) the expression of PD-L1, a coclinicaltrials.gov). inhibitory molecule that signals upon binding to PD-1 on the surface of CD8+ CTLs and (less so) NK cells; (3) the Importantly, NKG2A, NKG2D, and PD-1 are expressed by both NK cells and CD8+ CTLs, although to different degrees [1,3]. Moreover, recent data elucidated several aspects of the interaction between NK cells and dendritic cells (DCs) in the elicitation of anticancer immune responses. On the one hand, intratumoral NK cells have been shown to recruit type I conventional DCs, which are key for the crosspriming of CD8+ CTL-dependent anticancer immunity, to the tumor microenvironment and activate them, owing to their ability to secrete X-C motif chemokine ligand 1 (XCL1), C-C motif chemokine ligand 5 (CCL5), and fms-related tyrosine kinase 3 ligand (FLT3LG) [11,12]. On the on other hand, type I conventional DCs have been demonstrated to support the cytotoxic activity of NK cells by producing interleukin 12 (IL-12) [13]. 2
Trends in Cancer, Month Year, Vol. xx, No. yy
expression of HLA-A, HLA-B, and HLA-C to finely tuned degrees, which render cancer cells invisible to CD8+ CTLs and/or inhibit NK cell activation upon binding to killer cell immunoglobulin-like receptors (KIRs); and (4) the expression of metalloproteinases (MMPs) that shed NK cell activatory ligands from the cancer cell surface, which results in the production of soluble NK cell-activating ligands (sNKALs) operating as molecular decoys. All these mechanisms constitute potentially actionable targets to relieve immunosuppression in the tumor microenvironment and hence unleash the antitumor functions of NK cells and CD8+ CTLs. Abbreviation: TCR, T cell receptor.
Taken together, these findings delineate a complex network of interactions between innate and adaptive immune cells that underlie anticancer immunity. NK cells occupy multiple key positions in such network, offering various targets for therapeutic interventions (Figure 1). Given the elevated degree of redundancy that characterizes the immunosuppressive pathways activated in the tumor microenvironment, we surmise that only combinatorial strategies simultaneously actioning multiple of these targets will exhibit superior clinical efficacy.
Additional preclinical and clinical studies are urgently required to define the best approach to fight cancer with the help of both T cells and NK cells. Acknowledgments E.W. is supported by Breakthrough Fellowship Award from the U. S. Department of Defense (DoD) (W81XWH-17-1-0029). L.G. is supported by a Breakthrough Level 2 grant from the DoD, Breast Cancer Research Program (BC180476P1); by a startup grant from the Department of Radiation Oncology at Weill Cornell Medicine (New York, USA); by industrial collaborations with Lytix (Oslo, Norway) and Phosplatin (New York, USA); and by donations from Phosplatin
TRECAN 326 No. of Pages 3
(New York, USA), the Luke Heller TECPR2 Foundation (Massachusetts, USA), and Sotio a.s. (Prague, Czech Republic).
Disclaimer Statement L.G. provides remunerated consulting to OmniSEQ (Buffalo, NY, USA), Astra Zeneca (Gaithersburg, MD, USA), VL47 (New York, NY, USA), and the Luke Heller TECPR2 Foundation (Boston, MA, USA), and he is member of the Scientific Advisory Committee of OmniSEQ. 1 Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA 2 Sandra and Edward Meyer Cancer Center, New York, NY, USA 3 Université Paris Descartes, Sorbonne Paris Cité, Paris,
France
https://doi.org/10.1016/j.trecan.2018.12.005 © 2019 Elsevier Inc. All rights reserved.
References 1. Lopez-Soto, A. et al. (2017) Control of metastasis by NK cells. Cancer Cell 32, 135–154 2. Galluzzi, L. et al. (2018) The hallmarks of successful anticancer immunotherapy. Sci. Transl. Med. 10, eaat7807 3. Andre, P. et al. (2018) Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell 175, 1731–1743.e13 4. van Montfoort, N. et al. (2018) NKG2A blockade potentiates CD8 T cell immunity induced by cancer vaccines. Cell 175, 1744–1755.e15 5. Molgora, M. et al. (2017) IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity. Nature 551, 110–114 6. Ferrari de Andrade, L. et al. (2018) Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity. Science 359, 1537–1542
7. Lopez-Soto, A. et al. (2017) Soluble NKG2D ligands limit the efficacy of immune checkpoint blockade. Oncoimmunology 6, e1346766 8. Kohrt, H.E. et al. (2014) Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies. Blood 123, 678–686 9. Galluzzi, L. et al. (2015) Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 28, 690–714 10. Fournier, C. et al. (2017) Trial Watch: adoptively transferred cells for anticancer immunotherapy. Oncoimmunology 6, e1363139 11. Bottcher, J.P. et al. (2018) NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037 e1014 12. Barry, K.C. et al. (2018) A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat. Med. 24, 1178–1191 13. Mittal, D. et al. (2017) Interleukin-12 from CD103(+) Batf3dependent dendritic cells required for NK-cell suppression of metastasis. Cancer Immunol. Res. 5, 1098–1108
*Correspondence: [email protected] (E. Wennerberg) and [email protected] (L. Galluzzi).
Trends in Cancer, Month Year, Vol. xx, No. yy
3