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Roles for Innate Immunity in Combination Immunotherapies Kelly D

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Roles for Innate Immunity in Combination Immunotherapies Kelly D Published OnlineFirst September 19, 2017; DOI: 10.1158/0008-5472.CAN-17-1340 Cancer Review Research Roles for Innate Immunity in Combination Immunotherapies Kelly D. Moynihan1,2,3 and Darrell J. Irvine1,2,3,4,5 Abstract Immunity to infectious agents involves a coordinated especially in the context of combination immunotherapy, is response of innate and adaptive immune cells working in leading to novel strategies to elicit a more integrated immune concert, with many feed-forward and regulatory interactions response against cancer. Here we review antitumor activities of between both arms of the immune system. In contrast, many innate immune cells, mechanisms of their synergy with adap- therapeutic strategies to augment immunity against tumors tive immune responses against tumors, and discuss recent have focused predominantly on stimulation of adaptive immu- studies highlighting the potential of combination therapies nity. However, a growing appreciation of the potential con- recruiting both innate and adaptive immune effectors to erad- tributions of innate immune effectors to antitumor immunity, icate established tumors. Cancer Res; 77(19); 1–7. Ó2017 AACR. Introduction substitute for B cells (antitumor mAbs). However, natural immune responses are never based solely in adaptive immunity; The heterogeneity of human cancers combined with the diver- innate immune cells play an important role in complementing the sity of mechanisms acting in concert within established tumors to þ þ effector activities of CD4 and CD8 T cells, and provide unique suppress the immune response make it unlikely that any single- pathways to bolster an ongoing adaptive response. In this brief agent immunotherapy will elicit meaningful tumor regression in a review, we discuss pertinent features of innate responses to majority of patients—an expectation that has prompted the tumors, and examine findings from recent combination immu- search for safe and efficacious combination therapies. The count- notherapy studies that have revealed unexpected important roles less number of potential combination therapy permutations for innate immunity in successful antitumor therapies. possible even within the existing pool of immunotherapy drugs in early clinical testing motivates the need for rational approaches Roles of Innate Immune Effectors in to identify promising combination therapies. Progress in under- standing the tumor microenvironment and antitumor immunity Immunotherapy has led to the proposal that several functional steps are required Cells of the innate immune system are often described as for the immune response to eliminate established tumors, includ- having a dichotomous role in cancer, capable of both promoting ing blockade of immunosuppression, promotion of immune and inhibiting tumor growth, depending on the context. There is infiltration, induction of immunogenic tumor cell death, activa- mounting evidence that innate immune effectors can be driven to tion of antigen-presenting cells, and enhancement of effector cell impart antitumor immunity both directly and indirectly, given the activity (1–3). Identification of these target functional require- proper cues (Fig. 1). Dendritic cells (DC) play a critical role in ments sets the stage for designing combination treatments that immunotherapy by processing and presenting tumor antigens to address distinct barriers to tumor rejection. T cells, and their role in antitumor immune responses has been Many studies have focused on combination therapies that discussed in other recent reviews (4–7). Here we focus our promote complementary features of T-cell activity (e.g., treatment discussion here on four key functions of other innate immune with vaccines, antibodies blocking inhibitory receptors, and anti- cells that can have their own direct antitumor activity. bodies agonizing costimulatory receptors) or that synthetically Direct tumoricidal activities of innate cells Several innate immune cell populations, appropriately activat- 1Koch Institute for Integrative Cancer Research, Massachusetts Institute of ed, can directly kill tumor cells. Natural killer (NK) cells and NK T Technology, Cambridge, Massachusetts. 2Department of Biological Engineering, cells can recognize cell surface stress ligands and tumor-derived Massachusetts Institute of Technology, Cambridge, Massachusetts. 3Ragon glycolipids expressed by tumor cells, respectively, leading to Institute of Massachusetts General Hospital, Massachusetts Institute of Tech- innate cell activation and tumor cell lysis (4). Macrophages can nology, Cambridge, Massachusetts. 4Department of Materials Science and kill tumor cells through secretion of nitric oxide species (8). Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts. Activated eosinophils also exhibit tumoricidal activity through 5Howard Hughes Medical Institute, Chevy Chase, Maryland. the release of secretory granules containing multiple cytotoxic Corresponding Author: Darrell J. Irvine, Massachusetts Institute of Technology, molecules including membrane-disrupting major basic protein MIT Room 76-261, 77 Mass. Avenue, Cambridge, MA. Phone: 617-452-4174; Fax: and granzyme A, although mechanisms of tumor cell recognition 617-452-3293; E-mail: [email protected] by eosinophils remain undefined (9). Thus, immunotherapies doi: 10.1158/0008-5472.CAN-17-1340 stimulating these innate immune cell populations have the Ó2017 American Association for Cancer Research. potential to augment the cytotoxic activities of T cells. www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst September 19, 2017; DOI: 10.1158/0008-5472.CAN-17-1340 Moynihan and Irvine Influence the cytokine milieu of Engage in direct killing tumors, support adaptive responses Type I IFN, IL12, IL15 NK cells IFNγ Tumor CCL5, PMN Figure 1. granulocytes CXCL9, CXCL10 Roles of innate immune effectors in IFNγ Type I IFN, IL12, antitumor immunity. Innate immune CXCL9-11 effectors including NK cells, polymorphonuclear granulocyte-like Direct Tumor neutrophils and eosinophils, cytolysis, macrophages, and monocytes can ADCC, ADCP engage in direct tumoricidal activity ADCC Antigen presentation T cells respiratory burst, or exert Fc-mediated effector costimulation reactive nitrogen functions against antibody- species opsonized tumor cells utilizing multiple mechanisms (red). In MIP-1α, Dendritic Regulatory therapies with antibodies against MIP-2 cells targets overexpressed by Tregs, like T cell anti-CTLA-4, these FcgR-expressing effectors may also deplete Monocytes, Nitric oxide, CCL5 intratumoral Tregs. Tumor- macrophages infiltrating innate immune cells may also secrete factors that modulate the cytokine and chemokine milieu of the tumor (blue). FcγR Treg binding antibody Antitumor antibody Tumor-expressed ligands (ex. MIC-A) Recognition elements (ex. NKG2D) © 2017 American Association for Cancer Research Antibody-mediated killing of tumor cells Shaping the microenvironment of tumors Therapeutic mAbs have been approved for use in humans Innate immune cells can also play an important role in shaping against cancer for nearly two decades (10). Although many of the cytokine and chemokine milieu of the tumor microenviron- these were originally designed to antagonize oncogenic signaling ment, thus influencing DC activation and differentiation of effec- pathways, it has subsequently been shown that antibodies direct- tor T cells (4). Tumor-infiltrating neutrophils have been shown to ed against tumor surface antigens can recruit effector functions of engage in proimmunity cross-talk with T cells, secreting inflam- innate immune cells via interaction of the Fc region with FcgR- matory factors and expressing costimulatory molecules that bol- expressing cells, which can result in direct killing by multiple ster T-cell function and proliferation in a feed-forward loop (15). mechanisms. NK cells, neutrophils, and other myeloid cells can Intratumoral innate leukocytes can also undergo productive cross- kill through antibody-dependent cellular cytotoxicity (ADCC), a talk with other innate cells. For example, activated eosinophils process by which crosslinking of FcgRs by antibody-opsonized promote polarization of intratumoral macrophages toward an tumor cells results in the release of cytotoxic granules that contain M1 phenotype (16). In cetuximab-treated head and neck cancer perforin and granzyme (10). Both neutrophils and NK cells were patients, NK cells were shown to enhance therapy through inter- shown to be critical for ADCC-mediated elimination of CD52- actions with DCs, resulting in maturation and priming of anti- þ expressing tumor cells treated with the anti-CD52 antibody tumor CD8 T cells (17). This NK-DC cross-talk relied on the alemtuzumab (11), and in separate studies, FcgR-competent interaction of FcgRIIIa on NK cells with antibody-opsonized þ neutrophils were shown to be crucial effectors for antibody EGFR tumor cells, cytokines released by the cetuximab-activated therapy against syngeneic melanomas in mice (12). In addition NK cells, and NKG2D-MICA engagement, which in concert to mediating ADCC, macrophages can engulf and destroy tumor resulted in enhanced DC maturation and cross-presentation to cells through antibody-dependent cellular phagocytosis (ADCP; prime EGFR-specific T cells. ref. 13). Furthermore, opsonization of tumor cells with antitumor In addition, there is mounting preclinical evidence that check- antibodies can also lead
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