Cellular constituents of immune escape within the tumor microenvironment.

Established tumors are complex masses that contain not only neoplastic cells but also nontransformed cellular elements such as stromal cells, the neovasculature, and the full gamut of immune cells. However, evidence suggests that, unlike cells found in lymphoid organs that productively respond to acute infections, immune cells in tumors are dysregulated and functionally impaired. Tumor masses can contain regulatory lymphocytes, myeloid-derived suppressor cells, alternatively activated macrophages, and dendritic cells. Ablation or reprogramming of this aberrant microenvironment might dramatically augment cancer therapies, and this strategy is currently being deployed in a variety of clinical trials. A better understanding of the cellular constituents of tumors and the mechanisms involved in immune evasion may help guide the next generation of innovative cancer immunotherapies.

[1]  James O. Jones,et al.  Suppression of Antitumor Immunity by Stromal Cells Expressing , 2022 .

[2]  I. Fidler,et al.  AACR centennial series: the biology of cancer metastasis: historical perspective. , 2010, Cancer research.

[3]  P. Sinha,et al.  Myeloid-Derived Suppressor Cells: Linking Inflammation and Cancer 1 , 2009, The Journal of Immunology.

[4]  M. Karin,et al.  The unholy trinity: inflammation, cytokines, and STAT3 shape the cancer microenvironment. , 2011, Cancer Cell.

[5]  S. Rosenberg,et al.  The Use of Gene‐Modified Tumor‐Infiltrating Lymphocytes for Cancer Therapy , 1994, Annals of the New York Academy of Sciences.

[6]  A. Rudensky,et al.  Foxp3 programs the development and function of CD4+CD25+ regulatory T cells , 2003, Nature Immunology.

[7]  D. Carbone,et al.  Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells , 1996, Nature Medicine.

[8]  H. Heslop,et al.  Adoptive T cell therapy of cancer. , 2010, Current opinion in immunology.

[9]  Markus G. Manz,et al.  Development of Monocytes, Macrophages, and Dendritic Cells , 2010, Science.

[10]  E. Shevach.  Fatal attraction: tumors beckon regulatory T cells , 2004, Nature Medicine.

[11]  M. Young,et al.  Stimulation of immune-suppressive bone marrow cells by colony-stimulating factors. , 1990, Experimental hematology.

[12]  R. Steinman,et al.  Dendritic cells and the control of immunity , 1998, Nature.

[13]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[14]  G. Trinchieri,et al.  Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. , 2005, Cancer research.

[15]  D. Keskin,et al.  Potential Regulatory Function of Human Dendritic Cells Expressing Indoleamine 2,3-Dioxygenase , 2002, Science.

[16]  P. Hwu,et al.  Unopposed production of granulocyte-macrophage colony-stimulating factor by tumors inhibits CD8+ T cell responses by dysregulating antigen-presenting cell maturation. , 1999, Journal of immunology.

[17]  D. Munn,et al.  Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13. , 2010, Blood.

[18]  P. Sinha,et al.  Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. , 2010, Cancer research.

[19]  Paolo Serafini,et al.  Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. , 2006, The Journal of clinical investigation.

[20]  Eric C. Sorenson,et al.  Imatinib potentiates anti-tumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido , 2012 .

[21]  Drew M Pardoll,et al.  Cancer immunotherapy comes of age. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  J. Shimizu,et al.  Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. , 1999, Journal of immunology.

[23]  J. Jimenez,et al.  Expansion of immunoregulatory macrophages by granulocyte-macrophage colony-stimulating factor derived from a murine mammary tumor. , 1990, Cancer research.

[24]  R. North.  Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells , 1982, The Journal of experimental medicine.

[25]  A. Sica,et al.  Altered macrophage differentiation and immune dysfunction in tumor development. , 2007, The Journal of clinical investigation.

[26]  Jeffrey W. Pollard,et al.  Macrophage Diversity Enhances Tumor Progression and Metastasis , 2010, Cell.

[27]  Nina Bhardwaj,et al.  Antigen-Specific Inhibition of Effector T Cell Function in Humans after Injection of Immature Dendritic Cells , 2001, The Journal of experimental medicine.

[28]  L. Liotta,et al.  A model for CD8+ CTL tumor immunosurveillance and regulation of tumor escape by CD4 T cells through an effect on quality of CTL. , 1999, Journal of immunology.

[29]  S. Rosenberg,et al.  Local Delivery of lnterleukin-12 Using T Cells Targeting VEGF Receptor-2 Eradicates Multiple Vascularized Tumors in Mice , 2012, Clinical Cancer Research.

[30]  S. Rosenberg,et al.  Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[31]  Laurence Zitvogel,et al.  Immune parameters affecting the efficacy of chemotherapeutic regimens , 2011, Nature Reviews Clinical Oncology.

[32]  J. Allison,et al.  PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors , 2010, Proceedings of the National Academy of Sciences.

[33]  M. Sadelain,et al.  Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. , 2012, Blood.

[34]  S. Sakaguchi,et al.  CD4+ Tregs and immune control. , 2004, The Journal of clinical investigation.

[35]  F. Marincola,et al.  IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors. , 2011, The Journal of clinical investigation.

[36]  Craig Murdoch,et al.  The role of myeloid cells in the promotion of tumour angiogenesis , 2008, Nature Reviews Cancer.

[37]  S. Rosenberg,et al.  Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice. , 2010, The Journal of clinical investigation.

[38]  Alberto Mantovani,et al.  Macrophages, innate immunity and cancer: balance, tolerance, and diversity. , 2010, Current opinion in immunology.

[39]  C. June,et al.  Principles of adoptive T cell cancer therapy. , 2007, The Journal of clinical investigation.

[40]  D. Neuberg,et al.  A dual role for the immune response in a mouse model of inflammation-associated lung cancer. , 2011, The Journal of clinical investigation.

[41]  W. Zou.  Regulatory T cells, tumour immunity and immunotherapy , 2006, Nature Reviews Immunology.

[42]  B. Fingleton,et al.  Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. , 2004, Cancer cell.

[43]  P. Matzinger.  The Danger Model: A Renewed Sense of Self , 2002, Science.

[44]  T. Nomura,et al.  Control of Regulatory T Cell Development by the Transcription Factor Foxp3 , 2002 .

[45]  Hua Yu,et al.  STATs in cancer inflammation and immunity: a leading role for STAT3 , 2009, Nature Reviews Cancer.

[46]  V. Bronte,et al.  Tumor-induced immune dysfunctions caused by myeloid suppressor cells. , 2001, Journal of immunotherapy.

[47]  D. Schadendorf,et al.  Improved survival with ipilimumab in patients with metastatic melanoma. , 2010, The New England journal of medicine.

[48]  M. Noris,et al.  Natural versus adaptive regulatory T cells. , 2005, Contributions to nephrology.

[49]  George Coukos,et al.  Cancer immunotherapy comes of age , 2011, Nature.

[50]  H. Abken,et al.  IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively Muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression. , 2011, Cancer research.

[51]  E. El-Omar,et al.  Cancer and Inflammation: Promise for Biologic Therapy , 2010, Journal of immunotherapy.

[52]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.

[53]  R. Gershon,et al.  Cell interactions in the induction of tolerance: the role of thymic lymphocytes. , 1970, Immunology.

[54]  S. Rosenberg,et al.  Adoptive cell transfer: a clinical path to effective cancer immunotherapy , 2008, Nature Reviews Cancer.

[55]  S. Rosenberg.  The Development of New Immunotherapies for the Treatment of Cancer Using Interleukin‐2: A Review , 1988, Annals of surgery.

[56]  S. Rosenberg,et al.  Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells , 2005, The Journal of experimental medicine.

[57]  H. Schreiber,et al.  The role of stroma in immune recognition and destruction of well-established solid tumors. , 2006, Current opinion in immunology.

[58]  G. Trinchieri,et al.  Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. , 2010, Cancer research.

[59]  Ingo Fricke,et al.  Dendritic Cells and Tumor Microenvironment: A Dangerous Liaison , 2006, Immunological investigations.

[60]  H. Schreiber,et al.  Synergy between T-cell immunity and inhibition of paracrine stimulation causes tumor rejection. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[61]  L. Coussens,et al.  The tumor microenvironment: a critical determinant of neoplastic evolution. , 2003, European journal of cell biology.

[62]  N. Restifo,et al.  CD4+CD25+ T regulatory cells, immunotherapy of cancer, and interleukin-2. , 2005, Journal of immunotherapy.

[63]  C. Divino,et al.  Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. , 2006, Cancer research.

[64]  J. Wolchok,et al.  Novel cancer immunotherapy agents with survival benefit: recent successes and next steps , 2011, Nature Reviews Cancer.

[65]  M. Sadelain.  T-cell engineering for cancer immunotherapy. , 2009, Cancer journal.

[66]  S. Rosenberg,et al.  Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of Mac-1+/Gr-1+ cells. , 1998, Journal of immunology.

[67]  D. Gabrilovich.  Mechanisms and functional significance of tumour-induced dendritic-cell defects , 2004, Nature Reviews Immunology.

[68]  R. Schreiber,et al.  Cancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and Promotion , 2011, Science.

[69]  T. Fujita,et al.  Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. , 1999, Cancer research.

[70]  N. Ferrara,et al.  Role of myeloid cells in tumor angiogenesis and growth. , 2008, Trends in cell biology.

[71]  V. Bronte.  Myeloid‐derived suppressor cells in inflammation: Uncovering cell subsets with enhanced immunosuppressive functions , 2009, European journal of immunology.

[72]  Srinivas Nagaraj,et al.  Myeloid-derived suppressor cells as regulators of the immune system , 2009, Nature Reviews Immunology.