FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2294927533> ?p ?o ?g. }

• W2294927533 endingPage "1247" @default.
• W2294927533 startingPage "1233" @default.
• W2294927533 abstract "Cancer heterogeneity, a hallmark enabling clonal survival and therapy resistance, is shaped by active immune responses. Antigen-specific T cells can control cancer, as revealed clinically by immunotherapeutics such as adoptive T-cell transfer and checkpoint blockade. The host immune system is thus a powerful tool that, if better harnessed, could significantly enhance the efficacy of cytotoxic therapy and improve outcomes for cancer sufferers. To realize this vision, however, a number of research frontiers must be tackled. These include developing strategies for neutralizing tumor-promoting inflammation, broadening T-cell repertoires (via vaccination), and elucidating the mechanisms by which immune cells organize tumor microenvironments to regulate T-cell activity. Such efforts will pave the way for identifying new targets for combination therapies that overcome resistance to current treatments and promote long-term cancer control. Cancer heterogeneity, a hallmark enabling clonal survival and therapy resistance, is shaped by active immune responses. Antigen-specific T cells can control cancer, as revealed clinically by immunotherapeutics such as adoptive T-cell transfer and checkpoint blockade. The host immune system is thus a powerful tool that, if better harnessed, could significantly enhance the efficacy of cytotoxic therapy and improve outcomes for cancer sufferers. To realize this vision, however, a number of research frontiers must be tackled. These include developing strategies for neutralizing tumor-promoting inflammation, broadening T-cell repertoires (via vaccination), and elucidating the mechanisms by which immune cells organize tumor microenvironments to regulate T-cell activity. Such efforts will pave the way for identifying new targets for combination therapies that overcome resistance to current treatments and promote long-term cancer control. Cancer is an insidious disease traditionally classified by cell and tissue type of origin. Cancer has historically been treated according to a “one size fits all” approach based on broad pathologic criteria and involving various regimens of cytotoxic therapy. With the advent of modern sequencing methodologies, however, we now appreciate that significant genomic, transcriptomic, and epigenetic heterogeneity exists within individual tumor types; this recognition has enabled subclassification of tumors of common origin. This, in turn, has led to improved outcomes for some cancer types, as response rates to targeted and cytotoxic therapies increase when patients are stratified based on the molecular characteristics of their tumors. Examples include imatinib in chronic myelogenous leukemia (Druker et al., 2006Druker B.J. Guilhot F. O’Brien S.G. Gathmann I. Kantarjian H. Gattermann N. Deininger M.W. Silver R.T. Goldman J.M. Stone R.M. et al.IRIS InvestigatorsFive-year follow-up of patients receiving imatinib for chronic myeloid leukemia.N. Engl. J. Med. 2006; 355: 2408-2417Crossref PubMed Scopus (2453) Google Scholar), HER2-targeted therapies for HER2-positive breast cancer (Shepard et al., 1991Shepard H.M. Lewis G.D. Sarup J.C. Fendly B.M. Maneval D. Mordenti J. Figari I. Kotts C.E. Palladino Jr., M.A. Ullrich A. et al.Monoclonal antibody therapy of human cancer: taking the HER2 protooncogene to the clinic.J. Clin. Immunol. 1991; 11: 117-127Crossref PubMed Scopus (251) Google Scholar), and estrogen antagonists for estrogen-receptor-positive breast cancers (Heiser et al., 2012Heiser L.M. Sadanandam A. Kuo W.L. Benz S.C. Goldstein T.C. Ng S. Gibb W.J. Wang N.J. Ziyad S. Tong F. et al.Subtype and pathway specific responses to anticancer compounds in breast cancer.Proc. Natl. Acad. Sci. USA. 2012; 109: 2724-2729Crossref PubMed Scopus (234) Google Scholar). These molecular advances helped to usher in a new era of precision medicine that is reshaping clinical treatment across the cancer spectrum. However, there remain significant fractions of patients that do not respond to “designer” therapies even when their tumors are classified based on molecular and pathologic criteria. Additional tumor or systemic characteristic(s) are thus unaccounted for that not only impact neoplastic growth and dissemination, but also impact response to therapy. Recent seminal in vivo studies revealed that neoplastic cells rely on the diversity of normal resident and recruited accessory cells to support their evolution (Hanahan and Coussens, 2012Hanahan D. Coussens L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment.Cancer Cell. 2012; 21: 309-322Abstract Full Text Full Text PDF PubMed Scopus (1366) Google Scholar). Accessory cells are now recognized as “neoplastic cell-extrinsic hallmarks of cancer” and include those forming the hematogenous and lymphatic vasculature, tissue-specific mesenchymal support cells, and myeloid and lymphoid-lineage immune cells. Accessory cells integrate with the dynamic soluble and insoluble matrices constituting the “tumor stroma”; collectively, they fuel neoplastic evolution (Hanahan and Coussens, 2012Hanahan D. Coussens L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment.Cancer Cell. 2012; 21: 309-322Abstract Full Text Full Text PDF PubMed Scopus (1366) Google Scholar). In other words, reciprocal interactions between accessory cells, their mediators, structural components of the extracellular matrix (ECM), and genetically altered neoplastic cells regulate all aspects of tumorigenicity. These realizations fueled the development of anti-cancer agents targeting the vasculature (Kerbel, 2011Kerbel R. Anti-angiogenesis in cancer; met and unmet goals - an interview with Robert Kerbel by Francesco Bertolini.Int. J. Dev. Biol. 2011; 55: 395-398Crossref PubMed Scopus (0) Google Scholar) and, more recently, propelled clinical investigations into the efficacy of immune therapeutic approaches that neutralize tumor-promoting chronic inflammation and/or embolden or unleash cytotoxic activities of antigen-specific T cells (Coussens et al., 2013Coussens L.M. Zitvogel L. Palucka A.K. Neutralizing tumor-promoting chronic inflammation: a magic bullet?.Science. 2013; 339: 286-291Crossref PubMed Scopus (456) Google Scholar, Pardoll, 2012Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy.Nat. Rev. Cancer. 2012; 12: 252-264Crossref PubMed Scopus (4010) Google Scholar). Indeed, cancer is visible to the immune system, i.e., immunogenic, during early neoplasia. Classic studies from Schreiber and colleagues in mice with carcinogen-initiated sarcomas revealed that the immune system could recognize and reject cancerous cells (Dunn et al., 2004Dunn G.P. Old L.J. Schreiber R.D. The three Es of cancer immunoediting.Annu. Rev. Immunol. 2004; 22: 329-360Crossref PubMed Scopus (1408) Google Scholar). Elimination can be explained by cytotoxic antigen-specific T cells responding to relatively high mutational burdens induced by carcinogens and thus providing neo-antigens for T-cell priming; these findings established the principles of elimination, equilibrium, and eventually escape when neoplastic cells become invisible to the immune system (Dunn et al., 2004Dunn G.P. Old L.J. Schreiber R.D. The three Es of cancer immunoediting.Annu. Rev. Immunol. 2004; 22: 329-360Crossref PubMed Scopus (1408) Google Scholar). Neoplastic cells in part escape when tumor arises out of chronically inflamed tissues—there, chronic infiltration of tissue by leukocytes (e.g., type 2 cytokine-activated myeloid cells and immune-suppressive B, T, and myeloid subsets) subvert T-cell-directed elimination and thus aid tissue-based programs, e.g., angiogenesis, lymphangiogenesis, matrix remodeling, etc., supporting neoplastic progression (Coussens et al., 2013Coussens L.M. Zitvogel L. Palucka A.K. Neutralizing tumor-promoting chronic inflammation: a magic bullet?.Science. 2013; 339: 286-291Crossref PubMed Scopus (456) Google Scholar). Mounting observations in humans support the concept that cancer initiation and progression are significantly impacted by altered or misled immune responses (Figure 1). Individuals suffering from chronic inflammatory conditions are at increased risk for developing cancer (Thun et al., 2004Thun M.J. Henley S.J. Gansler T. Inflammation and cancer: an epidemiological perspective.Novartis Found. Symp. 2004; 256 (discussion 22–28, 49–52, 266–269): 6-21Crossref PubMed Google Scholar). Incidence of viral (DNA tumor virus) and carcinogen-associated cancers is increased in immune-compromised individuals, even as the relative risk of cancer types lacking viral or carcinogen etiology is diminished (reviewed in de Visser et al., 2006de Visser K.E. Eichten A. Coussens L.M. Paradoxical roles of the immune system during cancer development.Nat. Rev. Cancer. 2006; 6: 24-37Crossref PubMed Scopus (1368) Google Scholar). Age-related immunosenescence likely plays a role in increased incidence of malignancy in aged individuals (Campisi et al., 2011Campisi J. Andersen J.K. Kapahi P. Melov S. Cellular senescence: a link between cancer and age-related degenerative disease?.Semin. Cancer Biol. 2011; 21: 354-359PubMed Google Scholar). The advent of some biologic therapies impacting how tissues activate and resolve inflammation, e.g., tumor necrosis factor (TNF) blockade (Bongartz et al., 2006Bongartz T. Sutton A.J. Sweeting M.J. Buchan I. Matteson E.L. Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials.JAMA. 2006; 295: 2275-2285Crossref PubMed Scopus (1805) Google Scholar), also skews cancer incidence metrics. However, the role(s) that immune pathways play in driving malignancy remains to be clarified. How does the immune system recognize tissue-specific mediators triggering and maintaining chronic inflammatory responses? What oncogenic events and altered metabolic states lead to the generation of neo-antigens that in turn induce T-cell responses? What physiological mechanisms regulate immune homeostasis such that (acute) inflammation can be resolved as rapidly as it is activated (a critical control program to thwart autoimmunity)? What is the role of the host microbiota in regulating systemic immune responses to neoplasia? How do neoplastic cells survive immune attack by T cells? These questions are in need of answering to effectively move cancer research and cancer medicine forward. A common feature of all cancers, regardless of origin, is prominent presence of diverse assemblages of immune cells (Coussens et al., 2013Coussens L.M. Zitvogel L. Palucka A.K. Neutralizing tumor-promoting chronic inflammation: a magic bullet?.Science. 2013; 339: 286-291Crossref PubMed Scopus (456) Google Scholar). The consequences of such infiltrates on the fate of cancerous cells are diverse (Figure 2). For example, under continual immune pressure, i.e., antigen presentation to T cells, neoplastic cells become “immune-edited” to escape immune surveillance (Dunn et al., 2004Dunn G.P. Old L.J. Schreiber R.D. The three Es of cancer immunoediting.Annu. Rev. Immunol. 2004; 22: 329-360Crossref PubMed Scopus (1408) Google Scholar) and instead co-opt immune cells to favor their sustained proliferation (Balkwill et al., 2005Balkwill F. Charles K.A. Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease.Cancer Cell. 2005; 7: 211-217Abstract Full Text Full Text PDF PubMed Scopus (1156) Google Scholar). Nonetheless, recent studies demonstrate that the presence of lymphoid aggregates is linked with improved responses to cancer therapies—for example, standard cytotoxic therapies, vaccine-based treatments, or immune checkpoint blockade (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 (974) Google Scholar). Such “hot” tumors are thus more amenable to control than “cold” tumors, i.e., tumors with diminished T-cell infiltrates, thus driving modern cancer medicine to investigate how to reprogram the tumor microenvironment (TME) to attract the right type of immune infiltrate. This topic, along with other open questions in the field of oncoimmunology, are discussed here. Tumors are organized tissues with numerous reciprocal local and systemic connections with immune cell populations of both the myeloid and lymphoid lineages. Here, we summarize the key myeloid and lymphoid populations regulating the immune response to cancer and how the fundamental physiological processes that they govern are harnessed for neoplastic progression and tumor formation. Myeloid cells have multiple homeostatic functions that are co-opted by evolving neoplasms; these can be roughly summarized as: (1) antigen capture for degradation (macrophages) or presentation (dendritic cells [DCs]); (2) tissue repair (macrophages), and (3) effector functions (mast cells, monocytes, and granulocytes). Neoplastic cells can alter the steady-state activity of all myeloid cells present in the TME, including tissue-resident and blood-derived cells, by secreting factors such as interleukin (IL)-6 or granulocyte-macrophage colony-stimulating factor (GM-CSF), that increase recruitment and proliferation of immature myeloid cells atypical under physiological conditions (Gabrilovich et al., 2012Gabrilovich D.I. Ostrand-Rosenberg S. Bronte V. Coordinated regulation of myeloid cells by tumours.Nat. Rev. Immunol. 2012; 12: 253-268Crossref PubMed Scopus (1424) Google Scholar). An important feature of myeloid cells is their functional plasticity in response to environmental signals. This property can dictate such opposite outcomes as antigen degradation or antigen presentation when macrophages acquire DC capabilities (Banchereau et al., 2000Banchereau J. Briere F. Caux C. Davoust J. Lebecque S. Liu Y.J. Pulendran B. Palucka K. Immunobiology of dendritic cells.Annu. Rev. Immunol. 2000; 18: 767-811Crossref PubMed Scopus (5070) Google Scholar), tissue repair rather than inflammation when macrophages are polarized toward type 2 states, and protective or non-protective T-cell immunity when programmed by cancer-derived factors (Balkwill et al., 2005Balkwill F. Charles K.A. Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease.Cancer Cell. 2005; 7: 211-217Abstract Full Text Full Text PDF PubMed Scopus (1156) Google Scholar). Thus, plasticity and communication within the myeloid compartment and between myeloid and other immune cells and stromal components is critical for tumor formation. Cancer Antigen Presentation and Dendritic Cells. Cancer antigens are presented to T cells either at tumor sites or in draining lymph nodes by DCs (Figure 3). Cancer antigens, soluble and cell borne, are transported to lymph nodes via lymphatic vessels. Soluble antigen is captured by lymph-node-resident DCs, while tissue-resident DCs capture antigen at tumor sites; either population can present antigen locally or migrate through lymphatic vessels to present in lymph nodes (Steinman, 2011Steinman R. Cancer therapeutics: time to swim downstream?.Oncologist. 2011; 16: 1479-1480Crossref PubMed Google Scholar). DCs display protein antigens in the context of classical major histocompatibility (MHC) class I and MHC class II molecules or lipid antigens in the context of non-classical CD1 molecules that allow selection of rare antigen-specific T lymphocytes, including CD8+ T cells, CD4+ T cells, and NK T cells. Compared with other antigen-presenting cells (APCs), DCs are extremely efficient in their ability to induce antigen-specific T-cell responses, justifying their name “professional APCs” (Lanzavecchia and Sallusto, 2001Lanzavecchia A. Sallusto F. The instructive role of dendritic cells on T cell responses: lineages, plasticity and kinetics.Curr. Opin. Immunol. 2001; 13: 291-298Crossref PubMed Scopus (0) Google Scholar). Naive CD8+ T cells differentiate into cytotoxic T lymphocytes (CTLs) in lymphoid organs upon encounter with DCs, presenting tumor-derived peptides in the context of co-stimulation through CD80, CD70, and 4-1BB, as well as through DC-derived cytokines such as IL-12, type I interferon, and IL-15 (Steinman, 2012Steinman R.M. Decisions about dendritic cells: past, present, and future.Annu. Rev. Immunol. 2012; 30: 1-22Crossref PubMed Scopus (523) Google Scholar). The priming of new T-cell repertoires during tumorigenesis may be critical for clinical success of therapeutic agents aiming to unleash antigen-specific CTL activities. Naive CD4+ T cells can give rise to helper cells with distinct cytokine profiles or to Fox-P3+ regulatory T cells (Treg), whose role is to dampen CTL activity and avoid autoimmune responses (Zhu and Paul, 2008Zhu J. Paul W.E. CD4 T cells: fates, functions, and faults.Blood. 2008; 112: 1557-1569Crossref PubMed Scopus (802) Google Scholar). DCs express numerous pattern recognition receptors, including lectins, Toll-like receptors (TLRs), NOD-like receptors (NLRs), and helicases, through which they can sense microbes and tissue damage (cancer) such as increased pericellular nucleic acids (Pulendran, 2015Pulendran B. The varieties of immunological experience: of pathogens, stress, and dendritic cells.Annu. Rev. Immunol. 2015; 33: 563-606Crossref PubMed Scopus (42) Google Scholar). If DCs do not receive maturation signals, such as when exposed to high levels of IL-10 (Ruffell et al., 2014Ruffell B. Chang-Strachan D. Chan V. Rosenbusch A. Ho C.M. Pryer N. Daniel D. Hwang E.S. Rugo H.S. Coussens L.M. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells.Cancer Cell. 2014; 26: 623-637Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar), they remain immature and antigen presentation instead leads to T-cell suppression. DC plasticity in response to extrinsic signals, together with the existence of discrete subsets with unique functions, empowers DCs as key initiators and regulators of the immune response (Pulendran, 2015Pulendran B. The varieties of immunological experience: of pathogens, stress, and dendritic cells.Annu. Rev. Immunol. 2015; 33: 563-606Crossref PubMed Scopus (42) Google Scholar). We will illustrate this point briefly; mouse and human DC subset biology was recently reviewed elsewhere (Merad et al., 2013Merad M. Sathe P. Helft J. Miller J. Mortha A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting.Annu. Rev. Immunol. 2013; 31: 563-604Crossref PubMed Scopus (789) Google Scholar). The diversity of human DC subsets was revealed by studies of blood and skin DCs. Three main cell-surface markers distinguished human-blood-circulating DC subsets: CD303 (BDCA-2) on plasmacytoid DCs (pDCs), CD1c (or BDCA-1) expressed on the majority of circulating DCs, and CD141/BDCA-3 expressed on a small fraction (Merad et al., 2013Merad M. Sathe P. Helft J. Miller J. Mortha A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting.Annu. Rev. Immunol. 2013; 31: 563-604Crossref PubMed Scopus (789) Google Scholar). Human CD141+CD1c− DCs uniquely express TLR3, produce IL-12, and efficiently cross-prime CD8+ T cells when activated with poly I:C (Joffre et al., 2012Joffre O.P. Segura E. Savina A. Amigorena S. Cross-presentation by dendritic cells.Nat. Rev. Immunol. 2012; 12: 557-569Crossref PubMed Scopus (529) Google Scholar). However, other human DCs, such as epidermal Langerhans cells and CD1c+ DCs, also cross-present antigens to CD8+ T cells. Indeed, our studies have unraveled the basic principles by which human DC subsets differentially regulate CD8+ T cells (Klechevsky et al., 2008Klechevsky E. Morita R. Liu M. Cao Y. Coquery S. Thompson-Snipes L. Briere F. Chaussabel D. Zurawski G. Palucka A.K. et al.Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells.Immunity. 2008; 29: 497-510Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar). Thus, human Langerhans cells are highly efficient at priming cytotoxic CD8+ T cells, while CD14+ dermal DCs prime type 2 cytokine-secreting CD8+ T cells (Klechevsky et al., 2008Klechevsky E. Morita R. Liu M. Cao Y. Coquery S. Thompson-Snipes L. Briere F. Chaussabel D. Zurawski G. Palucka A.K. et al.Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells.Immunity. 2008; 29: 497-510Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar). Blood- and tissue-resident CD1c+ DCs, but not CD141+ DCs, exposed to live-attenuated influenza virus promote CD103 (αE integrin) expression on CD8+ T cells and their accumulation in epithelia (Yu et al., 2013Yu C.I. Becker C. Wang Y. Marches F. Helft J. Leboeuf M. Anguiano E. Pourpe S. Goller K. Pascual V. et al.Human CD1c+ dendritic cells drive the differentiation of CD103+ CD8+ mucosal effector T cells via the cytokine TGF-β.Immunity. 2013; 38: 818-830Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). The lymphoid compartment in tumors includes natural killer (NK) cells, γδ T cells, NK T cells, CD4+ T cells, CD8+ T cells, and B cells. Their functional activity depends upon expression of restriction elements, including peptide-MHC complexes (pMHC; for T cells), the MHC class I molecule (for NK cells), or surface proteins (for B-cell products, i.e., antibodies) that can be recognized in a specific manner. In addition, lymphoid cells can be induced to secrete different types of cytokines based on effector functions. For example, following an activating stimulus, TH1-polarized CD4+ T cells secrete IL-2, TNFα, and IFNγ; in conjunction with cytotoxic CD8+ T cells, they promote macrophage cytotoxic activity (Stout and Bottomly, 1989Stout R.D. Bottomly K. Antigen-specific activation of effector macrophages by IFN-gamma producing (TH1) T cell clones. Failure of IL-4-producing (TH2) T cell clones to activate effector function in macrophages.J. Immunol. 1989; 142: 760-765PubMed Google Scholar) and can induce upregulation of antigen processing and expression of MHCI and II molecules in professional APCs (i.e., macrophages and DCs). In contrast, expression of IL-4, -5, -6, -10, and -13 by TH2-polarized CD4+ T cells can induce T-cell anergy and loss of T-cell-mediated cytotoxicity, enhance humoral immunity, and regulate the tumor-promoting activities of macrophages (DeNardo et al., 2009DeNardo D.G. Barreto J.B. Andreu P. Vasquez L. Tawfik D. Kolhatkar N. Coussens L.M. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages.Cancer Cell. 2009; 16: 91-102Abstract Full Text Full Text PDF PubMed Scopus (678) Google Scholar). CD8+ T cells are considered the major anti-cancer effector cells, as they can give rise to CTLs that kill neoplastic cells presenting a specific pMHC complex (Appay et al., 2008Appay V. Douek D.C. Price D.A. CD8+ T cell efficacy in vaccination and disease.Nat. Med. 2008; 14: 623-628Crossref PubMed Scopus (246) Google Scholar). CTLs can be generated through either the priming of naive T cells or reprogramming of memory T cells. Naive CD8+ T cells differentiate into CTLs in lymphoid organs upon encounter with APCs presenting tumor-derived peptides in the context of appropriate co-stimulation and cytokine help. The ideal properties of anti-cancer CD8+ T cells include: high affinity for pMHC on tumor cells; high levels of cytotoxic mediators, e.g., granzymes A and B and perforin; expression of surface molecules, allowing trafficking into the tumor; and extended longevity and memory, thus enabling CTL generation upon antigen re-exposure (Appay et al., 2008Appay V. Douek D.C. Price D.A. CD8+ T cell efficacy in vaccination and disease.Nat. Med. 2008; 14: 623-628Crossref PubMed Scopus (246) Google Scholar). Memory T cells have long been described as two circulating populations: (1) central memory T cells that migrate between the secondary lymphoid organs and are capable of mounting proliferative responses on pathogen re-encounter and (2) effector memory T cells that traffic between blood and extralymphoid compartments for peripheral immune surveillance (Mueller et al., 2012Mueller S.N. Gebhardt T. Carbone F.R. Heath W.R. Memory T cell subsets, migration patterns, and tissue residence.Annu. Rev. Immunol. 2012; 31: 137-161Crossref PubMed Scopus (0) Google Scholar). Tissue-resident memory T cells are a third and phenotypically distinct category. Studies in mice and humans have revealed that this latter population can be superior to circulating central memory T cells at providing rapid long-term protection against re-infection (Sheridan and Lefrançois, 2011Sheridan B.S. Lefrançois L. Regional and mucosal memory T cells.Nat. Immunol. 2011; 12: 485-491Crossref PubMed Scopus (152) Google Scholar). Therefore, an active mechanism of peripheral T-cell retention likely exists not only to facilitate clearance of infected cells, but also to promote accumulation at sites having cleared an infectious virus. CD103/β7 integrin endows peripheral CD8+ T cells with a unique capacity to access epithelial compartments. Expression of CD103 on CTLs mediates adherence to E-cadherin and appears to be important in the final stages of neoplastic cell lysis and rejection (Le Floc’h et al., 2007Le Floc’h A. Jalil A. Vergnon I. Le Maux Chansac B. Lazar V. Bismuth G. Chouaib S. Mami-Chouaib F. Alpha E beta 7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis.J. Exp. Med. 2007; 204: 559-570Crossref PubMed Scopus (121) Google Scholar). Indeed, for mucosal cancer vaccines, homing to and retention of CD8+ T cells in mucosa is critical for efficacy (Sandoval et al., 2013Sandoval F. Terme M. Nizard M. Badoual C. Bureau M.F. Freyburger L. Clement O. Marcheteau E. Gey A. Fraisse G. et al.Mucosal imprinting of vaccine-induced CD8+ T cells is crucial to inhibit the growth of mucosal tumors.Sci. Transl. Med. 2013; 5: 172ra20Crossref PubMed Scopus (102) Google Scholar). Upon arrival in tumor beds, CD8+ T cells must confront numerous barriers, including intrinsic checkpoint regulators, such as CD28-CTLA-4, PD1-PD-L1, and immunoglobulin-like transcript receptors (ILTs) (Pardoll, 2012Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy.Nat. Rev. Cancer. 2012; 12: 252-264Crossref PubMed Scopus (4010) Google Scholar); extrinsic checkpoint regulators, such as Treg cells (Fehérvari and Sakaguchi, 2004Fehérvari Z. Sakaguchi S. CD4+ Tregs and immune control.J. Clin. Invest. 2004; 114: 1209-1217Crossref PubMed Scopus (333) Google Scholar) or myeloid cells (Gabrilovich et al., 2012Gabrilovich D.I. Ostrand-Rosenberg S. Bronte V. Coordinated regulation of myeloid cells by tumours.Nat. Rev. Immunol. 2012; 12: 253-268Crossref PubMed Scopus (1424) Google Scholar); a corrupted TME with protumor inflammation (Coussens et al., 2013Coussens L.M. Zitvogel L. Palucka A.K. Neutralizing tumor-promoting chronic inflammation: a magic bullet?.Science. 2013; 339: 286-291Crossref PubMed Scopus (456) Google Scholar); antigen loss and immune evasion of tumor targets (Klebanoff et al., 2011Klebanoff C.A. Acquavella N. Yu Z. Restifo N.P. Therapeutic cancer vaccines: are we there yet?.Immunol. Rev. 2011; 239: 27-44Crossref PubMed Scopus (186) Google Scholar); and tissue-specific alterations, such as fatty cells in breast cancer or desmofibrosis in pancreatic cancer stroma. Defining strategies for bypassing these obstacles and improving the clinical efficacy of T-cell therapies is the object of intense study. An important concept recently proposed by Mellman and colleagues is the cancer-immunity cycle (Chen and Mellman, 2013Chen D.S. Mellman I. Oncology meets immunology: the cancer-immunity cycle.Immunity. 2013; 39: 1-10Abstract Full Text Full Text PDF PubMed Scopus (1050) Google Scholar). It becomes apparent that any effective immune response against cancer will generate resistance via physiological pathways that evolved to protect tissue homeostasis. Here, we discuss how this cycle is altered in cancer pathogenesis and how it can be harnessed therapeutically. Clearly, combination therapies that intervene at several distinct pathways within the cancer-immunity cycle are needed to achieve cancer control. Unabated inflammation is a hallmark of cancer and is mediated by immune cells attracted to or residing at sites of neoplastic transformation (Balkwill et al., 2005Balkwill F. Charles K.A. Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease.Cancer Cell. 2005; 7: 211-217Abstract Full Text Full Text PDF PubMed Scopus (1156) Google Scholar). Indeed, immune cells are selectively recruited into early neoplastic tissues, likely in response to hard-wired pathways utilized by all tissues to resist/repair damage caused by bacterial, viral, or other pathogenic assaults. When successful, “initiated” pre-neoplastic cells are purged by the immune system (Dunn et al., 2004Dunn G.P. Old L.J. Schreiber R.D. The three Es of cancer immunoediting.Annu. Rev. Immunol. 2004; 22: 329-360Crossref PubMed Scopus (1408) Google Scholar). When the immune system fails, neoplastic cells are retained in “damaged” TMEs and provide a survival advantage resulting from abundant bioavailable mediators liberated as a function of tissue remodeling (Hanahan and Coussens, 2012Hanahan D. Coussens L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment.Cancer Cell. 2012; 21: 309-322Abstract Full Text Full Text PDF PubMed Scopus (1366) Google Scholar). Ensuing neoplastic progressio" @default.
• W2294927533 created "2016-06-24" @default.
• W2294927533 creator A5025353193 @default.
• W2294927533 creator A5058800155 @default.
• W2294927533 date "2016-03-01" @default.
• W2294927533 modified "2023-10-14" @default.
• W2294927533 title "The Basis of Oncoimmunology" @default.
• W2294927533 cites W1264670492 @default.
• W2294927533 cites W1525097199 @default.
• W2294927533 cites W1655698060 @default.
• W2294927533 cites W1765673603 @default.
• W2294927533 cites W1881610795 @default.
• W2294927533 cites W1897226866 @default.
• W2294927533 cites W1963904011 @default.
• W2294927533 cites W1965734808 @default.
• W2294927533 cites W1967060514 @default.
• W2294927533 cites W1969413249 @default.
• W2294927533 cites W1970712517 @default.
• W2294927533 cites W1978494950 @default.
• W2294927533 cites W1980942129 @default.
• W2294927533 cites W1982467804 @default.
• W2294927533 cites W1982998217 @default.
• W2294927533 cites W1987375206 @default.
• W2294927533 cites W1990400836 @default.
• W2294927533 cites W1993345471 @default.
• W2294927533 cites W1994993231 @default.
• W2294927533 cites W2007026865 @default.
• W2294927533 cites W2007417599 @default.
• W2294927533 cites W2011458181 @default.
• W2294927533 cites W2016967137 @default.
• W2294927533 cites W2017003957 @default.
• W2294927533 cites W2026578487 @default.
• W2294927533 cites W2026878412 @default.
• W2294927533 cites W2031866250 @default.
• W2294927533 cites W2031960993 @default.
• W2294927533 cites W2033820276 @default.
• W2294927533 cites W2035419373 @default.
• W2294927533 cites W2037801848 @default.
• W2294927533 cites W2044748328 @default.
• W2294927533 cites W2048270768 @default.
• W2294927533 cites W2049553585 @default.
• W2294927533 cites W2050927750 @default.
• W2294927533 cites W2052481226 @default.
• W2294927533 cites W2056628849 @default.
• W2294927533 cites W2057657815 @default.
• W2294927533 cites W2059128083 @default.
• W2294927533 cites W2060672294 @default.
• W2294927533 cites W2066013154 @default.
• W2294927533 cites W2066671159 @default.
• W2294927533 cites W2067509761 @default.
• W2294927533 cites W2067632426 @default.
• W2294927533 cites W2070220308 @default.
• W2294927533 cites W2076743146 @default.
• W2294927533 cites W2077672962 @default.
• W2294927533 cites W2079018735 @default.
• W2294927533 cites W2080645865 @default.
• W2294927533 cites W2085234652 @default.
• W2294927533 cites W2089187782 @default.
• W2294927533 cites W2091548845 @default.
• W2294927533 cites W2095940261 @default.
• W2294927533 cites W2096322385 @default.
• W2294927533 cites W2100142407 @default.
• W2294927533 cites W2101327682 @default.
• W2294927533 cites W2102033291 @default.
• W2294927533 cites W2104454069 @default.
• W2294927533 cites W2105011122 @default.
• W2294927533 cites W2106837613 @default.
• W2294927533 cites W2107268345 @default.
• W2294927533 cites W2107429737 @default.
• W2294927533 cites W2108929503 @default.
• W2294927533 cites W2111220263 @default.
• W2294927533 cites W2111975769 @default.
• W2294927533 cites W2116763454 @default.
• W2294927533 cites W2117246760 @default.
• W2294927533 cites W2120426523 @default.
• W2294927533 cites W2121626779 @default.
• W2294927533 cites W2122944628 @default.
• W2294927533 cites W2124632458 @default.
• W2294927533 cites W2127897152 @default.
• W2294927533 cites W2129311237 @default.
• W2294927533 cites W2130085747 @default.
• W2294927533 cites W2130192242 @default.
• W2294927533 cites W2131882149 @default.
• W2294927533 cites W2132361489 @default.
• W2294927533 cites W2132929600 @default.
• W2294927533 cites W2136964874 @default.
• W2294927533 cites W2139983295 @default.
• W2294927533 cites W2140703935 @default.
• W2294927533 cites W2142300779 @default.
• W2294927533 cites W2142530756 @default.
• W2294927533 cites W2142604595 @default.
• W2294927533 cites W2143413473 @default.
• W2294927533 cites W2143772132 @default.
• W2294927533 cites W2146440075 @default.
• W2294927533 cites W2151021631 @default.
• W2294927533 cites W2151055438 @default.
• W2294927533 cites W2153512326 @default.
• W2294927533 cites W2154594040 @default.

• next