ONCAlert | 2017 NANETS Symposium

The Tumor Microenvironment Mediates Immunotherapy Response

Erin M. Burns, PhD, MSPH
Published Online: 11:38 AM, Fri November 10, 2017
The tumor microenvironment (TME) consists of malignant and nontransformed cells and the associations between them. Nonmalignant cells exhibit tumor-promoting functions during all stages of carcinogenesis.1 Targeting nonmalignant cells and/or communication mediators may have immunotherapeutic application across various tumor types and could complement other therapies as well.2-4

Tumor Microenvironment

The TME is composed of a heterogeneous cell population that includes malignant cells and cells that support tumor proliferation, invasion, and metastatic potential though extensive crosstalk. Tumor-associated stromal cell populations, such as vascular endothelial cells, mesenchymal stromal cells, pericytes, fibroblasts, and adipocytes, are components of the TME. Resident cells of the TME express proangiogenic growth factors, proinflammatory cytokines, and matrix molecules, facilitating a dynamic tumor-promoting signaling network.5 Immune-infiltrating cells of innate and adaptive immunity generate an immunosuppressive microenvironment to facilitate cancer progression.

“The nonmalignant cells of the TME can comprise >50% of the mass of primary tumors and their metastases, but there are still many unanswered questions regarding their biology and function,” noted Frances R. Balkwill, OBE, of the Barts Cancer Institute, and colleagues in the Journal of Cell Science.6

The innate immune system rapidly responds to stimuli to spur long-lasting antigen-specific immunity, whereas the adaptive immune system is characterized by diversity, specificity, and memory5 (the adaptive immune system will be explained in further detail during a presentation by Jonathan Powell, MD, PhD, during the Primer). Innate immunity components include skin and mucosal membranes; pattern recognition receptors (PRRs), and humoral components including complement proteins and collectins. Innate effector cell types include monocytes, macrophages, dendritic cells (DCs), natural killer (NK) cells, and neutrophils. The activation of PRRs leads to a release of proinflammatory cytokines, contributing to dendritic cell maturation and antigen presentation to the adaptive immune system.6

Antineoplastic treatment may lead to the promotion of tumor-cell apoptosis, inflammation, and tumor-associated antigen (TAA) presentation with antitumor T-cell immunity activation.5 In growing tumors, persistent hypoxia upregulates the production of high mobility group box 1 (the HMGB1 protein), promoting angiogenesis and tumor growth by recruiting endothelial precursor cells and suppressive tumor-associated macrophages (TAMs).7 TAMs in the TME are characterized by the activated M2 phenotype and promote tumor cell growth and survival via immune suppression and tumor vascularization.8,9

As part of the innate immune system, the complement system is thought to have protective effects through both direct complement activation and tumor-antibody directed complementdependent cytotoxicity. In contrast, C5a generation in the TME attracts myeloid-derived suppressor cells (MDSCs) and induces reactive oxygen and nitrogen species generation, leading to impaired tumor-directed T-cell effects.10

“There is evidence that both acute and chronic inflammation may promote genetic abnormalities and cancer progression, suggesting that modulation of the innate immune system has the potential to impact our approach to cancer immunotherapy,” explained David B. Page, MD, of Memorial Sloan Kettering Cancer Center, and colleagues, in the Journal for ImmunoTherapy of Cancer.5

Many different populations of T cells are found within the TME, which is the focus of a presentation by Ana C. Anderson, PhD. Cytotoxic CD8-positive memory T cells are generally antigen-experienced, have tumor cell killing functions, and have been strongly associated with a good prognosis. 11 CD4-positive T helper 1 (TH1) cells support these CD8-positive T cells, and have been associated with a good prognosis when highly abundant within in the TME. CD4-positive TH2 cells and TH17 cells, which support B-cell responses and inflammation, respectively, have been associated with good outcomes in breast and esophageal cancers.12,13

Immunosuppressive T-regulatory cells (Tregs) are the CD4-positive T cells most frequently associated with tumor promotion.14 Through the production of interleukin-10, transforming growth factor beta (TGF-β), and cell-mediated contact through cytotoxic T-lymphocyte antigen-4 (CTLA-4), Tregs inhibit the immune system’s ability to recognize and clear tumor cells.14,15 A worse prognosis has been associated with an increased presence of Tregs in the TME in many cancer types.16-18 Their presence, however, has been associated with a good prognosis in Hodgkin lymphoma, which is attributed to direct tumor cell growth suppression.19-21

During T-cell activation, positive costimulatory receptors, including CD40, OX40, and CD137, are upregulated, allowing for differentiation into memory T cells and cytokine polarization. 22 Inhibitory receptors, such as programmed death-1 (PD-1) and CTLA-4, are induced following antigen encounters to limit immune system overstimulation. CTLA-4 is induced on CD4-positive T cells and CD8-positive T cells early after activation and is constitutively expressed on Tregs.23 Additionally, binding of CTLA-4 inhibits T-cell proliferation. PD-1 is expressed on activated NK cells, T cells, and B cells. PD-1 binds to its ligand, PD-L1, which is expressed by tumor and immune cells. B cells are commonly found in draining lymph nodes and lymphoid structures adjacent to the TME, but can also be found at tumor invasive margins. In some breast and ovarian cancers, B-cell infiltration into the TME has been associated with a favorable prognosis.24,25

NK cells and natural killer T (NKT) cells are innate cytotoxic lymphocytes that infiltrate the tumor stroma but do not come into direct contact with tumor cells. The presence of NK and NKT cells has been indicative of a good prognosis in colorectal and many other cancers.26 NK cells may not be able to exert their tumor-killing function, however, due to the induction of an anergic phenotype by TGF-β derived from malignant cells.11

Pro-tumorigenic activities of TAMs have been reported in most cancer types.27 TAMs have an important role in malignant cell migration, invasion, and metastases.28 The presence of TAMs in the microenvironment and the expression of genes associated with a strong macrophage signal are both correlated with a poor prognosis.29,30 The interaction between macrophages and the TME determines phenotypic response to environmental conditions. Many TAMs accumulate in hypoxic and necrotic areas of tumors as a result of hypoxia-induced chemoattractants, such as vascular endothelial growth factor.31 MDSCs are defined as inhibitory immune cells present in several cancer types. Because of a high degree of phenotypic variability and differentiation potential, characterization of MDSCs is complex.32 MDSCs have been shown to inhibit CD8-positive T-cell activation, induce Treg development, and modulate the polarization of macrophages to a TAM-like phenotype.33-36

DCs, which are important for antigen processing and presentation, and the topic of an early Primer presentation by A. Karolina Palucka, MD, PhD, are defective and unable to sufficiently stimulate an immune response to TAAs if they are found in the TME.36 The ability of DCs to activate immune functions is further impaired by the hypoxic and inflammatory TME. Furthermore, some DCs have been shown to suppress T-cell responses at the tumor site. Residential fibroblasts differentiate into myofibroblasts in response to tissue injury, which can cause organ fibrosis and enhance cancer development risk.37,38 Many TMEs contain large numbers of myofibroblasts, also known as cancer-associated fibroblasts (CAFs), which have many precursors, including smooth muscle cells, mesenchymal stem cells, and endothelial cells.39,40 CAFs secrete fibroblast growth factors, and in turn, TGF-β from fibroblasts induce epithelial-mesenchymal transition in malignant cells promoting an immune-suppressive microenvironment.41 Fibroblasts also secrete extracellular matrix components and remodeling enzymes that contribute to the composition of the TME.

How Tumor Cells Evade Immunosurveillance and Detection

“Some tumors effectively exclude the immune system,” explained Thomas Gajewski, MD, PhD, of the University of Chicago, in an interview with ScienceLife.42 “They hide from it or prevent T cells from invading. Others allow some mingling, an initial dialogue with the immune system, then suppress it. These 2 categories may require distinct immunotherapeutic interventions for optimal clinical effect.” Tumors can evade immune elimination using tumor-intrinsic and tumor-extrinsic mechanisms.5 Intrinsic mechanisms include major histocompatibility complex (MHC) loss, antigen loss, secretion of immunosuppressive cytokines, or expression of cell-surface markers that alter T-cell functionality. Extrinsic factors include geographic barriers, a variety of regulatory or suppressive immune cells (including Tregs), and a heterogeneous population of MDSCs and TAMs. Tregs may be targeted and depleted through the use of inhibitory antibodies, modification of trafficking, or T-cell plasticity exploitation.43 Ipilimumab (Yervoy), an anti−CTLA-4 immunotherapy, may function partially by depleting Tregs from the TME.44

By hiding tumor-specific antigens (TSAs), cancer cells can escape the host immune system. Specifically, immune cells search for cancer neoantigens, which are produced as a result of tumor-specific nonsynonymous mutations in gene-coding regions and are cross-presented by antigen-presenting cells.45 Recent studies demonstrated that tumor antigens are strongly correlated with both immunogenicity and response to anti−PD-1 immunotherapy.46-47 Cancer cells can evade the immune system and immunotherapies by reducing neoantigen expression. 48 Various molecular events can facilitate the loss of neoantigens, including the downregulation or loss of MHC class I proteins, which was confirmed in high-throughput studies.45,49,50 MHC class I proteins present small peptide antigens on cell surfaces and activate CD8-positive T cells via the T-cell receptor. T-cell epitopes associated with impaired peptide processing antigens presented by residual MHC class I molecules of cancer cells that have undergone immunoediting may be exploited using vaccination approaches.51

Other important mechanisms of immune escape include defects in TAP-1 and TAP-2 (transporter associated with antigen processing proteins) or beta-2 microglobulin that alter antigen processing.50,52 Antitumor responses can also be impacted by alterations in the interferon-gamma (IFN-γ) signaling pathway.53 Immune attacks may be dampened if cancer cells overexpress antiapoptotic proteins, such as Bcl-xL.54

Cancer cells produce immunoregulatory enzymes, immune checkpoint ligands, or immunosuppressive cytokines to modulate the efficacy and duration of the immune response, similarly to how MDSCs or Tregs present in the TME.55 TGF-β impairs the activation, maturation, or differentiation of innate and adaptive immune cells, including CD4-positive T cells, CD8-positive T cells, NK cells, dendritic cells, neutrophils, and macrophages.56 Furthermore, TGF-β inhibits cytotoxic T-cell functionality by altering expression of cytotoxic products such as IFN-γ.57,58 TGF-β has also been shown to inhibit differentiation into central memory T cells.59

The clinical success of many novel immunotherapies targeting immune checkpoints highlights the importance of associated ligands in regulating immune response.60 By expressing checkpoint molecules such as PD-L1, cancer cells can dampen immune response and prevent T-cell targeted cytotoxicity. T-cell activity is reduced upon surface-expressed PD-1 association with cognate PD-L1 molecules, eventually leading to an exhaustion state.51,61,62 T-cell activity can be partially restored through the introduction of inhibitory antibodies that block immune checkpoint functionality. The inflammatory cytokines IFN-γ and tumor necrosis factor-alpha can induce PD-L1 expression to limit the immune response in an inflammatory environment. Cancer cells encounter a variety of alterations and signals can modulate PD-L1 expression as an immunosuppression mechanism.63,64

In ex vivo experiments, MDSCs directly suppressed T-cell proliferation and are associated with poor survival outcomes following treatment with ipilimumab. M2-like TAMs contribute to the shaping of the TME through the secretion of cytokines related to tissue remodeling, enhanced invasion and metastasis, and increased immune suppression.65 Various compounds, including colony-stimulating factor 1 receptor, are under investigation for targeting and blocking MDSCs and TAMs; however, specificity remains a challenge.


The FDA has approved immune checkpoint inhibitors as pembrolizumab (Keytruda), nivolumab (Opdivo), and ipilimumab for treating a variety of cancer types.5 “Checkpoint- blockade immunotherapy has arguably been the most exciting advance made in cancer treatment in recent years,” Antoni Ribas, MD, PhD, of the University of California, Los Angeles, wrote in a recent perspective published in the New England Journal of Medicine.66 These antibodies dampen or shut down T-cell responses by binding to PD-1 or CTLA-4. Improved survival has been seen in various cancer types with these inhibitors and with combinations of inhibitors blocking both pathways.67

Cancer vaccines are designed to induce an adaptive immune response to a specific administered antigen, although unlike vaccines for preventing infectious disease, cancer vaccines are typically therapeutic.5 Identifying appropriate antigen targets for generating an effective antitumor response is challenging because tumor antigens may be either tumor associated or tumor specific. TAAs are present in many tumor cells, but may also be present in some normal cells. TSAs are antigens that are only found in tumors. Currently, few patients achieve tumor regression with cancer vaccines, potentially as a result of a lack of antigen-specific T-cell development, suboptimal selection of targeted antigens, suboptimal antitumor activity of vaccine-induced T cells, suppression of T cells by tumor-derived immunosuppressive signals, or prevention of activated T cells to enter the tumor.68

Adoptive cellular therapy involves manipulating autologous T cells outside of the body and reinfusing them into a patient to generate a robust antitumor response.5 T cells can be manipulated by gene insertion of a chimeric antigen receptor (CAR) or engineered T-cell receptor (TCR), or through expansion of endogenous tumor-infiltrating lymphocytes. CAR-engineered T cells can associate with tumors more readily and can be activated directly without antigen binding. Second-generation CARs have been enhanced using costimulatory domains. CAR T-cell therapy has contributed to a 90% complete remission rate in a population of primarily pediatric patients with acute lymphoblastic leukemia (ALL), which led to the approval of tisagenlecleucel (Kymriah) in this indication.69 This was followed by an approval for axicabtagene ciloleucel (Yescarta) for adult patients with relapsed or refractory non-Hodgkin lymphoma.

Using gene transfer technology, TCR genes can be introduced into T cells and promote an increased affinity against tumor-specific complexes. Unfortunately, this technique has not been successful in the clinic due to cross-reaction with cardiomyocyte proteins and development of severe neurologic adverse events.70-72 “Future questions in the field include how to combine adoptive T-cell therapy with other types of immunotherapy, how to scale up and streamline manufacturing, and the challenge of identifying novel targets with minimal ‘on-target, off-tumor’ toxicity,” noted Page and colleagues in the Journal for Immuno-Therapy of Cancer.5 Bispecific antibodies link the variable regions of 2 antibodies, leading to a construct that is specific to 2 agents. Blinatumomab (Blincyto), an antibody specific to both CD3 and CD19, has been approved by the FDA for adult and pediatric patients with relapsed or refractory B-cell ALL.73 Blinatumomab engages T cells with malignant CD19-positive leukemia clones, leading to T-cell activation and cytolysis of the leukemia cell. Understanding the interactions between the TME and immunotherapy facilitates the understanding of mechanisms of action and the development of new approaches. “As our knowledge about the TME and immunotherapy expands, more approaches will undoubtedly emerge to harness the TME and improve our current immunotherapies,” explained Haidong Tang, PhD, and colleagues of the University of Chicago, in Cancer Letters.74

  1. Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21(3):309-322. doi: 10.1016/j.ccr.2012.02.022.
  2. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883-899. doi: 10.1016/j.cell.2010.01.025.
  3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. doi: 10.1016/j.cell.2011.02.013.
  4. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436-444. doi: 10.1038/nature07205.
  5. Page DB, Bulua Bourla A, Daniyan A, et al. Tumor immunology and cancer immunotherapy: summary of the 2014 SITC primer. J Immunother Cancer. 2015;3:25. doi: 10.1186/s40425-015-0072-2.
  6. Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J Cell Sci. 2012;125(pt 23):5591-5596. doi: 10.1242/jcs.116392.
  7. Guo ZS, Liu Z, Bartlett DL, Tang D, Lotze MT. Life after death: targeting high mobility group box 1 in emergent cancer therapies. Am J Cancer Res. 2013;3(1):1-20.
  8. Murray PJ, Allen JE, Biswas SK, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41(1):14-20. doi: 10.1016/j.immuni.2014.06.008.
  9. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41(1):49-61. doi: 10.1016/j.immuni.2014.06.010.
  10. Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11(9):785-797. doi: 10.1038/ni.1923.
  11. Fridman WH, Pagès F, Sautès–Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298-306. doi: 10.1038/nrc3245.
  12. Yoon NK, Maresh EL, Shen D, et al. Higher levels of GATA3 predict better survival in women with breast cancer. Hum Pathol. 2010;41(12):1794-1801. doi: 10.1016/j.humpath.2010.06.010.
  13. Lv L, Pan K, Li XD, et al. The accumulation and prognosis value of tumor infiltrating IL-17 producing cells in esophageal squamous cell carcinoma. PLoS One. 2011;6(3):e18219. doi: 10.1371/journal.pone.0018219.
  14. Hsieh CS, Lee HM, Lio CW. Selection of regulatory T cells in the thymus. Nat Rev Immunol. 2012;12(3):157-167. doi: 10.1038/nri3155.
  15. Campbell DJ, Koch MA. Treg cells: patrolling a dangerous neighborhood. Nat Med. 2011;17(8):929-930. doi: 10.1038/nm.2433.
  16. Bates GJ, Fox SB, Han C, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006;24(34):5373-5380. doi: 10.1200/JCO.2006.05.9584.
  17. Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10(9):942-949. doi: 10.1038/nm1093.
  18. Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res. 2006;12(18):5423-5434. doi: 10.1158/1078-0432.CCR-06-0369.
  19. Fozza C, Longinotti M. T-cell traffic jam in Hodgkin's lymphoma: pathogenetic and therapeutic implications. Adv Hematol. 2011;2011:501659. doi: 10.1155/2011/501659.
  20. Koreishi AF, Saenz AJ, Persky DO, et al. The role of cytotoxic and regulatory T cells in relapsed/refractory Hodgkin lymphoma. Appl Immunohistochem Mol Morphol. 2010;18(3):206-211. doi: 10.1097/PAI.0b013
  21. Tzankov A, Meier C, Hirschmann P, Went P, Pileri SA, Dirnhofer S. Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin's lymphoma. Haematologica. 2008;93(2):193-200. doi: 10.3324/haematol.11702.
  22. Granier C, De Guillebon E, Blanc C, et al. Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer. ESMO Open. 2017;2(2):e000213. doi: 10.1136/esmoopen-2017-000213.
  23. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27(4):450-461. doi: 10.1016/j.ccell.2015.03.001.
  24. Coronella JA, Telleman P, Kingsbury GA, Truong TD, Hays S, Junghans RP. Evidence for an antigen-driven humoral immune response in medullary ductal breast cancer. Cancer Res. 2001;61(21):7889-7899.
  25. Milne K, Köbel M, Kalloger SE, et al. Systematic analysis of immune infiltrates in high-grade serous ovarian cancer reveals CD20, FoxP3 and TIA-1 as positive prognostic factors [Erratum in PLoS One. 2013;8(7)]. PLoS One. 2009;4(7):e6412. doi: 10.1371/journal.pone.0006412.
  26. Tachibana T, Onodera H, Tsuruyama T, et al. Increased intratumor Valpha24-positive natural killer T cells: a prognostic factor for primary colorectal carcinomas. Clin Cancer Res. 2005;11(20):7322-7327. doi: 10.1158/1078-0432.CCR-05-0877.
  27. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141(1):39-51. doi: 10.1016/j.cell.2010.03.014.
  28. Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006;124(2):263-266. doi: 10.1016/j.cell.006.01.007.
  29. Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol. 2002;196(3):254-265. doi: 10.1002/path.1027.
  30. Dave SS, Wright G, Tan B, et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med. 2004;351(21):2159-2169. doi: 10.1056/NEJMoa041869.
  31. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012;12(4):253-268. doi: 10.1038/nri3175.
  32. Murdoch C, Giannoudis A, Lewis CE. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood. 2004;104(8):2224-2234. doi: 10.1182/blood-2004-03-1109.
  33. Kusmartsev S, Nagaraj S, Gabrilovich DI. Tumor-associated CD8+ T cell tolerance induced by bone marrow-derived immature myeloid cells. J Immunol. 2005;175(7):4583-4592.
  34. Bronte V, Serafini P, Mazzoni A, Segal DM, Zanovello P. L-arginine metabolism in myeloid cells controls T-lymphocyte functions. Trends Immunol. 2003;24(6):302-306.
  35. Huang B, Pan PY, Li Q, 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. Cancer Res. 2006;66(2):1123-1131. doi: 10.1158/0008-5472.CAN-05-1299.
  36. Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol. 2007;179(2):977-983.
  37. Li B, Wang JH. Fibroblasts and myofibroblasts in wound healing: force generation and measurement. J Tissue Viability. 2011;20(4):108-120. doi: 10.1016/j.jtv.2009.11.004.
  38. Radisky DC, Kenny PA, Bissell MJ. Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem. 2007;101(4):830-839. doi: 10.1002/jcb.21186.
  39. Sugimoto H, Mundel TM, Kieran MW, Kalluri R. Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol Ther. 2006;5(12):1640-1646.
  40. Spaeth EL, Dembinski JL, Sasser AK, et al. Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS One. 2009;4(4):e4992. doi: 10.1371/journal.pone.0004992.
  41. Erez N, Truitt M, Olson P, Arron ST, Hanahan D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell. 2010;17(2):135-147. doi: 10.1016/j.ccr.2009.12.041.
  42. Easton J. Hiding in plain sight: how tumors evade our immune system. ScienceLife/University of Chicago Medicine website. sciencelife.uchospitals.edu/2013/09/18/hiding-in-plain-sight-how-tumors-evade-our-immune-system/. Published September 18, 2013. Accessed August 11, 2017.
  43. Oleinika K, Nibbs RJ, Graham GJ, Fraser AR. Suppression, subversion and escape: the role of regulatory T cells in cancer progression. Clin Exp Immunol. 2013;171(1):36-45. doi: 10.1111/j.1365-2249.2012.04657.x.
  44. Simpson TR, Li F, Montalvo-Ortiz W, et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells codefines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med. 2013;210(9):1695-1710. doi: 10.1084/jem.20130579.
  45. Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160(1-2):48-61. doi: 10.1016/j.cell.2014.12.033.
  46. McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351(6280):1463-1469. doi: 10.1126/science.aaf1490.
  47. Rizvi NA, Hellmann MD, Snyder A, et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124-128. doi: 10.1126/science.aaa1348.
  48. Anagnostou V, Smith KN, Forde PM, et al. Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer. Cancer Discov. 2017;7(3):264-276. doi: 10.1158/2159-8290.CD-16-0828.
  49. Garrido F, Cabrera T, Aptsiauri N. “Hard” and “soft” lesions underlying the HLA class I alterations in cancer cells: implications for immunotherapy. Int J Cancer. 2010;127(2):249-256. doi: 10.1002/ijc.25270.
  50. Korkolopoulou P, Kaklamanis L, Pezzella F, Harris AL, Gatter KC. Loss of antigen-presenting molecules (MHC class I and TAP-1) in lung cancer. Br J Cancer. 1996;73(2):148-153.
  51. van der Burg SH, Arens R, Ossendorp F, van Hall T, Melief CJ. Vaccines for established cancer: overcoming the challenges posed by immune evasion. Nat Rev Cancer. 2016;16(4):219-233. doi: 10.1038/nrc.2016.16.
  52. del Campo AB, Kyte JA, Carretero J, et al. Immune escape of cancer cells with beta2-microglobulin loss over the course of metastatic melanoma. Int J Cancer. 2014;134(1):102-113. doi: 10.1002/ijc.28338.
  53. Gao J, Shi LZ, Zhao H, et al. Loss of IFN-gamma pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell. 2016;167(2):397-404.e9. doi: 10.1016/j.cell.2016.08.069.
  54. Terry S, Savagner P, Ortiz-Cuaran S, et al. New insights into the role of EMT in tumor immune escape. Mol Oncol. 2017;11(7):824-846. doi: 10.1002/1878-0261.12093.
  55. Tu E, Chia PZ, Chen W. TGFβ in T cell biology and tumor immunity: angel or devil? Cytokine Growth Factor Rev. 2014;25(4):423-435. doi: 10.1016/j.cytogfr.2014.07.014.
  56. Joffroy CM, Buck MB, Stope MB, Popp SL, Pfizenmaier K, Knabbe C. Antiestrogens induce transforming growth factor beta-mediated immunosuppression in breast cancer. Cancer Res. 2010;70(4):1314-1322. doi: 10.1158/0008-5472.CAN-09-3292.
  57. Thomas DA, Massague J. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell. 2005;8(5):369-380. doi: 10.1016/j.ccr.2005.10.012.
  58. Takai S, Schlom J, Tucker J, Tsang KY, Greiner JW. Inhibition of TGF-beta1 signaling promotes central memory T cell differentiation. J Immunol. 2013;191(5):2299-2307. doi: 10.4049/jimmunol.1300472.
  59. Burstein HJ, Krilov L, Aragon-Ching JB, et al. Clinical cancer advances 2017: Annual Report on Progress Against Cancer from the American Society of Clinical Oncology. J Clin Oncol. 2017;35(12):1341-1367. doi: 10.1200/JCO.2016.71.5292.
  60. Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016;8(328):328rv4. doi: 10.1126/scitranslmed.aad7118.
  61. Crespo J, Sun H, Welling TH, Tian Z, Zou W. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol. 2013;25(2):214-221. doi: 10.1016/j.coi.2012.12.003.
  62. Chen J, Jiang CC, Jin L, Zhang XD. Regulation of PD-L1: a novel role of pro-survival signalling in cancer. Ann Oncol. 2016;27(3):409-416. doi: 10.1093/annonc/mdv615.
  63. O'Donnell JS, Smyth MJ, Teng MW. Acquired resistance to anti-PD1 therapy: checkmate to checkpoint blockade? Genome Med. 2016;8(1):111. doi: 10.1186/s13073-016-0365-1.
  64. Cook J, Hagemann T. Tumour-associated macrophages and cancer. Curr Opin Pharmacol. 2013;13(4):595-601. doi: 10.1016/j.coph.2013.05.017.
  65. Ribas A. Releasing the brakes on cancer immunotherapy. N Engl J Med. 2015;373(16):1490-1492. doi: 10.1056/NEJMp1510079.
  66. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107(9):4275-4280. doi: 10.1073/pnas.0915174107.
  67. Feig C, Jones JO, Kraman M, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013;110(50):20212-20217. doi: 10.1073/pnas.1320318110.
  68. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507-1517. doi: 10.1056/NEJMoa1407222.
  69. Linette GP, Stadtmauer EA, Maus MV, et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood. 2013;122(6):863-871. doi: 10.1182/blood-2013-03-490565.
  70. Cameron BJ, Gerry AB, Dukes J, et al. Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci Transl Med. 2013;5(197):197ra103. doi: 10.1126/scitranslmed.3006034.
  71. Morgan RA, Chinnasamy N, Abate-Daga D, et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother. 2013;36(2):133-151. doi: 10.1097/CJI.0b013e3182829903.
  72. Topp MS, Gokbuget N, Zugmaier G, et al. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014;32(36):4134-4140. doi: 10.1200/JCO.2014.56.3247.
  73. Tang H, Qiao J, Fu YX. Immunotherapy and tumor microenvironment. Cancer Lett. 2016;370(1):85-90. doi: 10.1016/j.canlet.2015.10.009.

Copyright © TargetedOnc 2017 Intellisphere, LLC. All Rights Reserved.