Oncolytic Viruses as Antigen-Agnostic Cancer Vaccines
2018; Cell Press; Volume: 33; Issue: 4 Linguagem: Inglês
10.1016/j.ccell.2018.03.011
ISSN1878-3686
AutoresStephen J. Russell, Glen N. Barber,
Tópico(s)Animal Virus Infections Studies
ResumoSelective destruction of neoplastic tissues by oncolytic viruses (OVs) leads to antigen-agnostic boosting of neoantigen-specific cytotoxic T lymphocyte (CTL) responses, making OVs ideal companions for checkpoint blockade therapy. Here we discuss the mechanisms whereby OVs modulate both adjuvanticity and antigenicity of tumor cells. Suppression of antitumor immunity after OV therapy has not been observed, possibly because viral antigen expression diminishes as the antiviral response matures, thereby progressively honing the CTL response to tumor neoantigens. By combining direct in situ tumor destruction with the ability to boost antitumor immunity, OVs also have the potential to be powerful standalone cancer therapies. Selective destruction of neoplastic tissues by oncolytic viruses (OVs) leads to antigen-agnostic boosting of neoantigen-specific cytotoxic T lymphocyte (CTL) responses, making OVs ideal companions for checkpoint blockade therapy. Here we discuss the mechanisms whereby OVs modulate both adjuvanticity and antigenicity of tumor cells. Suppression of antitumor immunity after OV therapy has not been observed, possibly because viral antigen expression diminishes as the antiviral response matures, thereby progressively honing the CTL response to tumor neoantigens. By combining direct in situ tumor destruction with the ability to boost antitumor immunity, OVs also have the potential to be powerful standalone cancer therapies. Oncolytic viruses (OVs) are replication competent viruses that selectively propagate in tumor cells and/or in the immunosuppressive tumor microenvironment. Because of their intrinsic antigenicity, tumors are a priori evolved to evade immune detection, and have sluggish or defective pathogen-associated molecular pattern (PAMP) and damage-associated molecular pattern (DAMP) responses, which make them especially susceptible to virus infections (Galluzzi et al., 2017Galluzzi L. Buque A. Kepp O. Zitvogel L. Kroemer G. Immunogenic cell death in cancer and infectious disease.Nat. Rev. Immunol. 2017; 17: 97-111Crossref PubMed Scopus (1478) Google Scholar, Xia et al., 2016Xia T. Konno H. Barber G.N. Recurrent loss of STING signaling in melanoma correlates with susceptibility to viral oncolysis.Cancer Res. 2016; 76: 6747-6759Crossref PubMed Scopus (185) Google Scholar). However, to increase their utility as anticancer agents, OVs are generally engineered or adapted to further increase their antitumor specificity, safety, immunogenicity, oncolytic potency, and druggability, and the list of virus platforms adapted for oncolytic applications is rapidly growing (Maroun et al., 2017Maroun J. Munoz-Alia M. Ammayappan A. Schulze A. Peng K.-W. Russell S. Designing and building oncolytic viruses.Future Virol. 2017; 12: 193-213Crossref PubMed Scopus (86) Google Scholar). Irrespective of the status of the molecular signaling machinery in a tumor and the degree to which it reprograms an immune privileged microenvironment, introducing an OV does cause cellular damage, eventually inducing pro-inflammatory DAMP and PAMP responses, and promoting phagocytosis of dead or injured virus-infected tumor cells (Chiocca and Rabkin, 2014Chiocca E.A. Rabkin S.D. Oncolytic viruses and their application to cancer immunotherapy.Cancer Immunol. Res. 2014; 2: 295-300Crossref PubMed Scopus (242) Google Scholar). The weaker the innate and adaptive immune responses to the intratumoral virus infection, the more extensive its spread and the more damage it causes (Liu et al., 2014Liu Y.P. Wang J. Avanzato V.A. Bakkum-Gamez J.N. Russell S.J. Bell J.C. Peng K.W. Oncolytic vaccinia virotherapy for endometrial cancer.Gynecol. Oncol. 2014; 132: 722-729Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, Ruotsalainen et al., 2015Ruotsalainen J.J. Kaikkonen M.U. Niittykoski M. Martikainen M.W. Lemay C.G. Cox J. De Silva N.S. Kus A. Falls T.J. et al.Clonal variation in interferon response determines the outcome of oncolytic virotherapy in mouse CT26 colon carcinoma model.Gene Ther. 2015; 22: 65-75Crossref PubMed Scopus (26) Google Scholar). Thus, a virus infection in a tumor typically ends up breaking tolerance and eliciting innate and adaptive immune responses that result in its ultimate elimination. Although there is enormous diversity in the structures and replication strategies of known viruses, they have all evolved to keep their infected cell substrates alive long enough to manufacture virus progeny and, therefore, encode combat proteins that control cell death and limit the emission of danger signals from infected cells (Finlay and McFadden, 2006Finlay B.B. McFadden G. Anti-immunology: evasion of the host immune system by bacterial and viral pathogens.Cell. 2006; 124: 767-782Abstract Full Text Full Text PDF PubMed Scopus (595) Google Scholar). Speed of replication and stealth in the face of innate and adaptive immune responses also help viruses to complete their life cycle before the infected cell has time to mount an effective response. But these are only temporary holding measures that serve to slow, but not stop, the crescendo of innate and adaptive host immune responses. Thus, depending on its immunogenicity, genome complexity, speed of intratumoral propagation, and capacity for controlling host responses, a given OV may spread more or less extensively in a tumor before it is contained. Sometimes, where a profoundly unresponsive and immunosuppressive tumor is invaded by a rapidly propagating OV, the infection can spread sufficiently to destroy the entire tumor (Naik et al., 2012Naik S. Nace R. Federspiel M.J. Barber G.N. Peng K.W. Russell S.J. Curative one-shot systemic virotherapy in murine myeloma.Leukemia. 2012; 26: 1870-1878Crossref PubMed Scopus (64) Google Scholar, Russell et al., 2014Russell S.J. Federspiel M.J. Peng K.W. Tong C. Dingli D. Morice W.G. Lowe V. O'Connor M.K. Kyle R.A. Leung N. et al.Remission of disseminated cancer after systemic oncolytic virotherapy.Mayo Clin. Proc. 2014; 89: 926-933Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar). However, partial tumor damage is more typical and the recent surge of interest in oncolytic virotherapy is on account of its potential ability to reprogram the tumor microenvironment during this destructive phase in such a way as to boost systemic antitumor immunity, thereby providing an ideal accompaniment to immune checkpoint blockade (Guo et al., 2017Guo Z.S. Liu Z. Kowalsky S. Feist M. Kalinski P. Lu B. Storkus W.J. Bartlett D.L. Oncolytic immunotherapy: conceptual evolution, current strategies, and future perspectives.Front. Immunol. 2017; 8: 555Crossref PubMed Scopus (60) Google Scholar, Lichty et al., 2014Lichty B.D. Breitbach C.J. Stojdl D.F. Bell J.C. Going viral with cancer immunotherapy.Nat. Rev. Cancer. 2014; 14: 559-567Crossref PubMed Scopus (433) Google Scholar). Recent clinical experience with first generation OVs has confirmed their druggability and anticancer potential (Russell and Peng, 2017Russell S.J. Peng K.W. Oncolytic virotherapy: a contest between apples and oranges.Mol. Ther. 2017; 25: 1107-1116Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). T-VEC, an attenuated herpes simplex virus incorporating a granulocyte-macrophage colony-stimulating factor (GM-CSF) transgene, was granted US and European marketing approvals in 2015 for intratumoral therapy in patients with unresectable stage 3 and 4 melanoma. Approval was based on a 16% durable remission rate and modest survival prolongation in the phase 3 registration trial (Andtbacka et al., 2015aAndtbacka R.H. Kaufman H.L. Collichio F. Amatruda T. Senzer N. Chesney J. Delman K.A. Spitler L.E. Puzanov I. Agarwala S.S. et al.Talimogene laherparepvec improves durable response rate in patients with advanced melanoma.J. Clin. Oncol. 2015; 33: 2780-2788Crossref PubMed Scopus (1060) Google Scholar), with complete resolution rate of 47% for injected skin lesions versus only 9% for deep visceral lesions (Andtbacka et al., 2016Andtbacka R.H. Ross M. Puzanov I. Milhem M. Collichio F. Delman K.A. Amatruda T. Zager J.S. Cranmer L. Hsueh E. et al.Patterns of clinical response with talimogene laherparepvec (T-VEC) in patients with melanoma treated in the OPTiM phase III clinical trial.Ann. Surg. Oncol. 2016; 23: 4169-4177Crossref PubMed Scopus (200) Google Scholar). Virus did not spread from injected to uninjected lesions, and visceral lesion responses were attributed to boosting of systemic antitumor immunity. T-VEC was subsequently combined with ipilimumab (anti-CTLA4) and increased the overall response rate from 18% with ipilimumab alone to 39% with combination therapy in a 200-patient randomized phase 2 melanoma trial (Chesney et al., 2017Chesney J. Puzanov I. Collichio F. Singh P. Milhem M.M. Glaspy J. Hamid O. Ross M. Friedlander P. Garbe C. et al.Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma.J. Clin. Oncol. 2017; https://doi.org/10.1200/JCO.2017.73.7379Crossref Scopus (375) Google Scholar). An even higher overall response rate of 68% was reported when T-VEC was combined with the anti-PD1 antibody pembrolizumab, with 33% of patients achieving complete disease remission (Ribas et al., 2017Ribas A. Dummer R. Puzanov I. VanderWalde A. Andtbacka R.H.I. Michielin O. Olszanski A.J. Malvehy J. Cebon J. Fernandez E. et al.Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy.Cell. 2017; 170: 1109-1119 e1110Abstract Full Text Full Text PDF PubMed Scopus (861) Google Scholar). Aside from T-VEC, several additional non-herpes virus oncolytics are showing early clinical promise. Tumor responses have been achieved following intratumoral or locoregional administration of oncolytic strains of vaccinia virus, coxsackievirus A21 (CVA21), vesicular stomatitis virus, measles virus, poliovirus, C-type retrovirus, adenovirus, and other viruses in early stage clinical trials in a range of cancer types, and, in many cases, there is evidence that these responses are at least partially immune mediated (Guo et al., 2017Guo Z.S. Liu Z. Kowalsky S. Feist M. Kalinski P. Lu B. Storkus W.J. Bartlett D.L. Oncolytic immunotherapy: conceptual evolution, current strategies, and future perspectives.Front. Immunol. 2017; 8: 555Crossref PubMed Scopus (60) Google Scholar, Russell and Peng, 2017Russell S.J. Peng K.W. Oncolytic virotherapy: a contest between apples and oranges.Mol. Ther. 2017; 25: 1107-1116Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). For example, an intraperitoneally administered measles virus boosted the immune response to known ovarian tumor antigens in patients with refractory ovarian cancer (Galanis et al., 2015Galanis E. Atherton P.J. Maurer M.J. Knutson K.L. Dowdy S.C. Cliby W.A. Haluska Jr., P. Long H.J. Oberg A. Aderca I. et al.Oncolytic measles virus expressing the sodium iodide symporter to treat drug-resistant ovarian cancer.Cancer Res. 2015; 75: 22-30Crossref PubMed Scopus (130) Google Scholar) and strong evidence of synergy was observed using intratumoral CVA21 in combination with checkpoint antibody therapy for melanoma therapy (Andtbacka et al., 2015bAndtbacka R.H.I. Curti B.D. Kaufman H. Daniels G.A. Nemunaitis J.J. Spitler L.E. Hallmeyer S. Lutzky J. Schultz S.M. Whitman E.D. et al.Final data from CALM: a phase II study of Coxsackievirus A21 (CVA21) oncolytic virus immunotherapy in patients with advanced melanoma.J. Clin. Oncol. 2015; 33https://doi.org/10.1200/JCO.2014.58.3377Crossref PubMed Scopus (1585) Google Scholar). In light of the observation that T-VEC injected tumors are more likely to respond than distant metastases, emphasis is rapidly shifting from intratumoral to intravenous OV delivery. For a variety of reasons (size, manufacturing, high seroprevalence), intravenous use of HSV-based oncolytics may be problematic. However, feasibility for the systemic approach has been well documented for several OV families in preclinical cancer models and is gaining traction in the clinic. In one compelling demonstration of the potential power of the approach, complete resolution of multiple plasmacytomas and clearance of diffuse bone marrow infiltration were documented in a patient with treatment-refractory multiple myeloma following a single intravenous infusion of a recombinant measles virus (Russell et al., 2014Russell S.J. Federspiel M.J. Peng K.W. Tong C. Dingli D. Morice W.G. Lowe V. O'Connor M.K. Kyle R.A. Leung N. et al.Remission of disseminated cancer after systemic oncolytic virotherapy.Mayo Clin. Proc. 2014; 89: 926-933Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar). Systemic antitumor activity has also been documented for reovirus, adenovirus, CVA21, VSV, vaccinia, and Newcastle disease virus oncolytics (Russell et al., 2012Russell S.J. Peng K.W. Bell J.C. Oncolytic virotherapy.Nat. Biotechnol. 2012; 30: 658-670Crossref PubMed Scopus (962) Google Scholar), and some of these agents have already advanced to combination studies with checkpoint antibody therapy. Cancers displaying immunogenic peptide-MHC complexes (neoantigens, oncofetal antigens, or other tumor-associated antigens, hereafter referred to as TAA) are potentially vulnerable to TAA-reactive cytotoxic T lymphocyte (CTL), but are often protected from CTL-mediated lysis through upregulation of inhibitory immune checkpoints (Topalian et al., 2015Topalian S.L. Drake C.G. Pardoll D.M. Immune checkpoint blockade: a common denominator approach to cancer therapy.Cancer Cell. 2015; 27: 450-461Abstract Full Text Full Text PDF PubMed Scopus (2618) Google Scholar). This protection can be reversed by immune checkpoint blockade therapy using antibodies reactive with PD-1, PD-L1, or CTLA-4, which have recently gained FDA approvals for therapy of melanoma, lung cancer, kidney, bladder, and head and neck cancers, Hodgkin's lymphoma, and microsatellite unstable malignancies (Alexander, 2016Alexander W. The checkpoint immunotherapy revolution: what started as a trickle has become a flood, despite some daunting adverse effects; new drugs, indications, and combinations continue to emerge.P T. 2016; 41: 185-191PubMed Google Scholar, Salama and Moschos, 2017Salama A.K. Moschos S.J. Next steps in immuno-oncology: enhancing antitumor effects through appropriate patient selection and rationally designed combination strategies.Ann. Oncol. 2017; 28: 57-74Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). In general, cancers responsive to checkpoint blockade have a higher mutational burden, and hence more neoantigens, than those that are non-responsive. Unfortunately, many patients have a low precursor frequency of TAA-reactive T cells and respond poorly to checkpoint blockade due to paucity of antigen presentation on tumor cells and/or weak adjuvanticity of tumor cell death in an immunosuppressive tumor microenvironment (Schumacher and Schreiber, 2015Schumacher T.N. Schreiber R.D. Neoantigens in cancer immunotherapy.Science. 2015; 348: 69-74Crossref PubMed Scopus (2981) Google Scholar). Simply restating the above, the mode of action of immune checkpoint blockade is to remove the inhibitory signals that tumor cells present to their would-be executioner CTLs. The potency of checkpoint inhibitor antibodies is therefore limited by the number of TAA-reactive CTLs available to attack the tumor. Thus, if OV therapy were to increase the number of available tumor-reactive CTLs, it should also boost the response to checkpoint antibody therapy. Available preclinical and clinical evidence support this mechanism (Bartee and Li, 2017Bartee E. Li Z. In vivo and in situ programming of tumor immunity by combining oncolytics and PD-1 immune checkpoint blockade.Exp. Hematol. Oncol. 2017; 6: 15Crossref PubMed Scopus (6) Google Scholar, Chesney et al., 2017Chesney J. Puzanov I. Collichio F. Singh P. Milhem M.M. Glaspy J. Hamid O. Ross M. Friedlander P. Garbe C. et al.Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma.J. Clin. Oncol. 2017; https://doi.org/10.1200/JCO.2017.73.7379Crossref Scopus (375) Google Scholar, Durham et al., 2017Durham N.M. Mulgrew K. McGlinchey K. Monks N.R. Ji H. Herbst R. Suzich J. Hammond S.A. Kelly E.J. Oncolytic VSV primes differential responses to immuno-oncology therapy.Mol. Ther. 2017; 25: 1917-1932Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, Engeland et al., 2014Engeland C.E. Grossardt C. Veinalde R. Bossow S. Lutz D. Kaufmann J.K. Shevchenko I. Umansky V. Nettelbeck D.M. Weichert W. et al.CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy.Mol. Ther. 2014; 22: 1949-1959Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, Gao et al., 2009Gao Y. Whitaker-Dowling P. Griffin J.A. Barmada M.A. Bergman I. Recombinant vesicular stomatitis virus targeted to Her2/neu combined with anti-CTLA4 antibody eliminates implanted mammary tumors.Cancer Gene Ther. 2009; 16: 44-52Crossref PubMed Scopus (47) Google Scholar, Puzanov et al., 2016Puzanov I. Milhem M.M. Minor D. Hamid O. Li A. Chen L. Chastain M. Gorski K.S. Anderson A. Chou J. et al.Talimogene laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIB-IV melanoma.J. Clin. Oncol. 2016; 34: 2619-2626Crossref PubMed Scopus (371) Google Scholar, Ribas et al., 2017Ribas A. Dummer R. Puzanov I. VanderWalde A. Andtbacka R.H.I. Michielin O. Olszanski A.J. Malvehy J. Cebon J. Fernandez E. et al.Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy.Cell. 2017; 170: 1109-1119 e1110Abstract Full Text Full Text PDF PubMed Scopus (861) Google Scholar, Shen et al., 2016Shen W. Patnaik M.M. Ruiz A. Russell S.J. Peng K.W. Immunovirotherapy with vesicular stomatitis virus and PD-L1 blockade enhances therapeutic outcome in murine acute myeloid leukemia.Blood. 2016; 127: 1449-1458Crossref PubMed Scopus (86) Google Scholar, Woller et al., 2015Woller N. Gurlevik E. Fleischmann-Mundt B. Schumacher A. Knocke S. Kloos A.M. Saborowski M. Geffers R. Manns M.P. Wirth T.C. et al.Viral infection of tumors overcomes resistance to PD-1-immunotherapy by broadening neoantigenome-directed T-cell responses.Mol. Ther. 2015; 23: 1630-1640Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar) and further demonstrate that OV-mediated upregulation of the PD-1/PD-L1 axis in virus-infected tumors can be overridden by checkpoint antibodies (Samson et al., 2018Samson A. Scott K.J. Taggart D. West E.J. Wilson E. Nuovo G.J. Thomson S. Corns R. Mathew R.K. Fuller M.J. et al.Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade.Sci. Transl. Med. 2018; 10https://doi.org/10.1126/scitranslmed.aam7577Crossref PubMed Scopus (233) Google Scholar). Below we discuss our current understanding of the impact of OV infection both on adjuvanticity and antigenicity of dead or dying tumor cells and how this primes and amplifies the available pool of tumor-killing TAA-reactive CTLs. Whether priming a new antitumor response or boosting a pre-existing response, to amplify TAA-reactive CTL tumor-resident dendritic cells (DCs) must phagocytose, process, and cross-present tumor antigens, migrate to lymphoid follicles, and coordinate the engagement, activation, and amplification of helper T cells along with CTLs (Vyas et al., 2008Vyas J.M. Van der Veen A.G. Ploegh H.L. The known unknowns of antigen processing and presentation.Nat. Rev. Immunol. 2008; 8: 607-618Crossref PubMed Scopus (445) Google Scholar). The helper T cells interact with MHC class 2-peptide complexes on the DC surface and release cytokines that drive the proliferation of CTLs interacting with MHC class 1-peptide complexes also presented by the DC. In a tumor responding to conventional therapy, this entire process may fail due to lack of adjuvanticity at the site of tumor cell death, or due to lack of antigenicity of the dying tumor cells (Galluzzi et al., 2017Galluzzi L. Buque A. Kepp O. Zitvogel L. Kroemer G. Immunogenic cell death in cancer and infectious disease.Nat. Rev. Immunol. 2017; 17: 97-111Crossref PubMed Scopus (1478) Google Scholar). Tumor cells typically die by apoptosis, which is relatively non-inflammatory and lacks adjuvanticity, such that tumor-resident DCs are not sufficiently activated to phagocytose dying cells, process and present peptides, or migrate to regional lymph nodes, and new DC progenitors are not recruited (Woo et al., 2015Woo S.R. Corrales L. Gajewski T.F. Innate immune recognition of cancer.Annu. Rev. Immunol. 2015; 33: 445-474Crossref PubMed Scopus (344) Google Scholar). Also, tumor-resident macrophages may have been irreversibly programmed by long association with the tumor cells to actively promote the generation of antigen-specific suppressor T cells capable of damping down the antitumor CTL response (Dehne et al., 2017Dehne N. Mora J. Namgaladze D. Weigert A. Brune B. Cancer cell and macrophage cross-talk in the tumor microenvironment.Curr. Opin. Pharmacol. 2017; 35: 12-19Crossref PubMed Scopus (147) Google Scholar, Gordon et al., 2017Gordon S.R. Maute R.L. Dulken B.W. Hutter G. George B.M. McCracken M.N. Gupta R. Tsai J.M. Sinha R. Corey D. et al.PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity.Nature. 2017; 545: 495-499Crossref PubMed Scopus (1086) Google Scholar, Hou et al., 2016Hou W. Sampath P. Rojas J.J. Thorne S.H. Oncolytic virus-mediated targeting of PGE2 in the tumor alters the immune status and sensitizes established and resistant tumors to immunotherapy.Cancer Cell. 2016; 30: 108-119Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, Nagata and Tanaka, 2017Nagata S. Tanaka M. Programmed cell death and the immune system.Nat. Rev. Immunol. 2017; 17: 333-340Crossref PubMed Scopus (255) Google Scholar). In the following sections we discuss the impact of OV infection on these two critical parameters of adjuvanticity and antigenicity. Unlike their uninfected counterparts, OV-infected tumor cells undergo inflammatory death, their PAMPs and DAMPs having been activated as a consequence of virus inflicted damage, their apoptotic cell death pathways blocked, and their necroptotic cell death machinery activated (Kaminskyy and Zhivotovsky, 2010Kaminskyy V. Zhivotovsky B. To kill or be killed: how viruses interact with the cell death machinery.J. Intern. Med. 2010; 267: 473-482Crossref PubMed Scopus (74) Google Scholar, Schock et al., 2017Schock S.N. Chandra N.V. Sun Y. Irie T. Kitagawa Y. Gotoh B. Coscoy L. Winoto A. Induction of necroptotic cell death by viral activation of the RIG-I or STING pathway.Cell Death Differ. 2017; 24: 615-625Crossref PubMed Scopus (89) Google Scholar). Considerable evidence has recently emerged to support the superiority of necroptotic death as a driver of anticancer immunity, and the mechanisms by which the various known DAMPs boost tumor cell adjuvanticity have been comprehensively reviewed elsewhere (Galluzzi et al., 2017Galluzzi L. Buque A. Kepp O. Zitvogel L. Kroemer G. Immunogenic cell death in cancer and infectious disease.Nat. Rev. Immunol. 2017; 17: 97-111Crossref PubMed Scopus (1478) Google Scholar, Krysko et al., 2017Krysko O. Aaes T.L. Kagan V.E. D'Herde K. Bachert C. Leybaert L. Vandenabeele P. Krysko D.V. Necroptotic cell death in anti-cancer therapy.Immunol. Rev. 2017; 280: 207-219Crossref PubMed Scopus (108) Google Scholar). In brief, released ATP enhances the recruitment of DCs and their activation; annexin A1 guides the final approach of DCs to dying tumor cells; calreticulin and phosphatidylserine exposed on the cell surface act as “eat me” signals promoting phagocytosis; HMGB1 drives DC maturation; type I interferons (IFNs) increase the expression of MHC-peptide complexes and promote the intratumoral release of CXCL10, a T cell chemokine. Although beyond the scope of this review, it should be noted that, not only do apoptosis and necroptosis come in many (more or less immunogenic) forms, but there are in addition several alternative cell death pathways that can be activated in a virus-infected tumor cell, adding further complication to the analysis of forces sculpting the antitumor immune response (Galluzzi et al., 2018Galluzzi L. Vitale I. Aaronson S.A. Abrams J.M. Adam D. Agostinis P. Alnemri E.S. Altucci L. Amelio I. Andrews D.W. et al.Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018.Cell Death Differ. 2018; 25: 486-541Crossref PubMed Scopus (2651) Google Scholar). Irrespective of their propensity to cause necroptosis, OVs activate PAMPs in infected cancer cells, which drives adjuvanticity independent of the mode of cell death (Schock et al., 2017Schock S.N. Chandra N.V. Sun Y. Irie T. Kitagawa Y. Gotoh B. Coscoy L. Winoto A. Induction of necroptotic cell death by viral activation of the RIG-I or STING pathway.Cell Death Differ. 2017; 24: 615-625Crossref PubMed Scopus (89) Google Scholar). A further consideration is that many virus-infected cancer cells in the tumor microenvironment are likely eaten alive, and die not by necroptosis but by phagoptosis inside the phagocytosing macrophage or DC (Brown and Neher, 2012Brown G.C. Neher J.J. Eaten alive! Cell death by primary phagocytosis: 'phagoptosis'.Trends Biochem. Sci. 2012; 37: 325-332Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar). Thus, as discussed below, in oncolytic virotherapy, tumor cell PAMPs may be more important drivers of adjuvanticity and effective antigen-presenting cell (APC) engagement than the mode of cell death. When tumor cells are killed by viruses, both the adjuvanticity and antigenicity of the phagocytosed tumor cells are driven by their cellular contents. The body has evolved processes to efficiently eliminate apoptotic cells via phagocytosis while at the same time ensuring that there are no inflammatory counter reactions (Nagata and Tanaka, 2017Nagata S. Tanaka M. Programmed cell death and the immune system.Nat. Rev. Immunol. 2017; 17: 333-340Crossref PubMed Scopus (255) Google Scholar). This is impressive, since up to 50 billion apoptotic cells are efficiently processed by phagocytes on a daily basis (Toda et al., 2015Toda S. Nishi C. Yanagihashi Y. Segawa K. Nagata S. Clearance of apoptotic cells and pyrenocytes.Curr. Top. Dev. Biol. 2015; 114: 267-295Crossref PubMed Scopus (17) Google Scholar). Tumor cells almost certainly mimic this non-innate immune provoking death pathway, after engulfment, which helps them to become immunologically indolent (Mohme et al., 2017Mohme M. Riethdorf S. Pantel K. Circulating and disseminated tumour cells - mechanisms of immune surveillance and escape.Nat. Rev. Clin. Oncol. 2017; 14: 155-167Crossref PubMed Scopus (321) Google Scholar, Nagata and Tanaka, 2017Nagata S. Tanaka M. Programmed cell death and the immune system.Nat. Rev. Immunol. 2017; 17: 333-340Crossref PubMed Scopus (255) Google Scholar, Toda et al., 2015Toda S. Nishi C. Yanagihashi Y. Segawa K. Nagata S. Clearance of apoptotic cells and pyrenocytes.Curr. Top. Dev. Biol. 2015; 114: 267-295Crossref PubMed Scopus (17) Google Scholar). After phagocytosis, tumor cell nucleic acid is proficiently digested by DNases before it can robustly activate innate immune pathways and trigger cytokine production, including type I IFNs, which are required to stimulate cross-priming events and facilitate antitumor T cell activity (Nagata and Tanaka, 2017Nagata S. Tanaka M. Programmed cell death and the immune system.Nat. Rev. Immunol. 2017; 17: 333-340Crossref PubMed Scopus (255) Google Scholar, Schiavoni et al., 2013Schiavoni G. Mattei F. Gabriele L. Type I interferons as stimulators of DC-mediated cross-priming: impact on anti-tumor response.Front. Immunol. 2013; 4: 483Crossref PubMed Scopus (88) Google Scholar). A key challenge has therefore been to convert such “cold tumors” into “hot” or immunologically reactive ones. OVs are able to do this in a number of ways. For example, first the infection of the tumor cell itself may trigger innate immune signaling and alert the immunosurveillance system to the infected tumor microenvironment (Barber, 2011Barber G.N. Innate immune DNA sensing pathways: STING, AIMII and the regulation of interferon production and inflammatory responses.Curr. Opin. Immunol. 2011; 23: 10-20Crossref PubMed Scopus (193) Google Scholar, Franz and Kagan, 2017Franz K.M. Kagan J.C. Innate immune receptors as competitive determinants of cell fate.Mol. Cell. 2017; 66: 750-760Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, Takeuchi and Akira, 2009Takeuchi O. Akira S. Innate immunity to virus infection.Immunol. Rev. 2009; 227: 75-86Crossref PubMed Scopus (910) Google Scholar). Second, tumor cells infected with viruses are full of cytosolic PAMPs in the form of microbial nucleic acid. Following engulfment, the phagocyte degradation machinery likely gets overwhelmed by the “eaten” microbial-specific molecules/nucleic acid, which interact with extrinsic innate immune sensors to generate cytokines required for cross-priming and adaptive immunity (Nagata and Tanaka, 2017Nagata S. Tanaka M. Programmed cell death and the immune system.Nat. Rev. Immunol. 2017; 17: 333-340Crossref PubMed Scopus (255) Google Scholar, Schiavoni et al., 2013Schiavoni G. Mattei F. Gabriele L. Type I interferons as stimulators of DC-mediated cross-priming: impact on anti-tumor response.Front. Immunol. 2013; 4: 483Crossref PubMed Scopus (88) Google Scholar). The key innate immune pathways and sensors have now been largely uncovered. For example, Toll-like receptor (TLR) TLR
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