BMS - IO Pathway

Through our deep understanding of immunobiology, we have focused on multiple categories of immune mechanisms that can help restore the body’s natural ability to fight cancer.

We’re investigating multiple approaches in each category. As most tumors use more than one immune suppression mechanism or develop new mechanisms over the course of the disease, we continue to investigate how signaling pathways interact and work to identify combination strategies that may activate an effective immune response.

Explore a pathway under investigation.

Effector cells are central to antitumor
immunity. Effector cell antitumor
activity can be held in check by three
ways that exploit normal immune
mechanisms.

Select a category on the wheel to begin.

Tumor

The TUMOR may leverage inherent mechanisms to sustain itself and evade immune destruction.

Activate effector T cells

Effector T cells are the primary weapons of the adaptive immune system, and are responsible for finding and destroying cancer cells in the body. Targeting select immune mechanisms may help stimulate the production of T cells and boost the immune system’s ability to respond to cancer.

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Enhance NK-cell activity

NK-cells are the effector cells of the innate immune system. When engaged by activating receptors in the tumor microenvironment, NK-cells can recognize tumor cells as foreign and target them for destruction.

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Inhibit/target tumor cell pathways

Certain pathways in the tumor microenvironment are responsible for stimulating or perpetuating tumor cell growth and survival. Targeting these pathways may help inhibit tumor growth and potentially promote antitumor activity.

Block tumor inhibition/checkpoints

There are several mechanisms that prevent the immune system from attacking healthy cells, but in some cases, these can be manipulated by the tumor in order to evade the immune response. Blocking these pathways may help release the breaks on the immune system, allowing the effector cells to attack the cancer.

Immune regulatory cells & APCs

IMMUNE REGULATORY and ANTIGEN PRESENTING CELLS may negatively regulate or not provide necessary stimulation in the immune system.

Block or deplete immune regulators

Immune regulators function to suppress T cell activity, or promote regulatory T cell (Treg) activity, which prevents the immune system from over-responding to threats, but some tumors use these mechanisms to avoid detection. Blocking or depleting these pathways may help reverse this immunosuppressive activity, allowing the immune system to more effectively respond to the cancer.

Optimize antigen presentation

In some tumors, a decrease in antigen presentation can be a key mechanism of immune escape. Promoting antigen presentation in the tumor microenvironment is believed to help stimulate T cell activity and initiate an antitumor response.

Stroma

The STROMA comprises a variety of cell types that may suppress immune function via expression of cell surface or soluble inhibitory molecules, including metabolites.

Block inhibitory stromal effects

Stromal cells can act as a barrier that prevents immune-cell infiltration of the tumor. Blocking these mechanisms may help impede immuno-
suppressive cells from infiltrating the tumor microenvironment, and in turn, help the immune system recognize the cancer.

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Innate immune activators

The innate immune system mediates the presentation of tumor antigens, priming and activation of tumor-specific immune cells that enable optimal development of adaptive antitumor immunity. Targeting mechanisms involved in the innate immune response may potentially lead to the activation of dendritic cells and priming tumor-targeted T cells.

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Effector cells are central to antitumor immunity. Effector cell antitumor activity can be held in check by three ways that exploit normal immune mechanisms.

Tumor
The TUMOR may leverage inherent mechanisms to sustain itself and evade immune destruction.

Stroma
The STROMA comprises a variety of cell types that may suppress immune function via expression of cell surface or soluble inhibitory molecules, including metabolites.

Immune regulatory cells & APCs
IMMUNE REGULATORY and ANTIGEN PRESENTING CELLS may negatively regulate or not provide necessary stimulation in the immune system.

Through our deep understanding of immunobiology, we have focused on multiple categories of immune mechanisms that can help restore the body’s natural ability to fight cancer.

We’re investigating multiple approaches in each category. As most tumors use more than one immune suppression mechanism or develop new mechanisms over the course of the disease, we continue to investigate how signaling pathways interact and work to identify combination strategies that may activate an effective immune response.

Select a mechanism name for more information.

Select a mechanism name for more information.

Select a mechanism name for more information.

CD27

  • CD27 is an activating receptor found on the surface of T cells and other immune cell subsets1
  • CD27 plays a role in immune regulation, including the proliferation, function and survival of cytotoxic T cells, as well as the differentiation of memory T cells2-5
  • Based on preclinical data, activation of CD27 signaling can augment cytotoxic T cell function and the maintenance of long-term immune responses6
References
  • 1. Nolte MA, van Olffen RW, van Gisbergen KP, van Lier RA. Timing and tuning of C027-C070 interactions: the impact of signal strength in setting the balance between adaptive responses and immunopathology. lmmunol Rev. 2009;229(1):216-231.
  • 2. Hendricks J, Gravestein LA, Tesselaar K, et al. CD27 is required for generation and long-term maintenance of T cell immunity. Nat Immunol. 200;1(5):433-44D.
  • 3. Hendricks J. Xiao Y, Borst J. CD27 promotes survival of activated T cells and complements CD 28 in generation and establishment of the effector T cell pool. J Exp Med. 2003;198(9):1369-1380.
  • 4. Rowley TF, Al-Shamkhani A. Stimulation by soluble CD 70 promotes strong primary and secondary CD8+ cytotoxic T cell responses in vivo. J IMMUNOL. 1995;154(8):3686-3695. 6. He LZ. Prostak N, Thomas LJ, et al. Agonist anti-human CD27 monoclonal antibody induces T cell activation and tumor immunity in human CD27-transgenic mice. J Immunol. 2013;191(8):4174-4183.
  • 5. Brown GR, Meek K, Nishioka Y, Thiele DL. CD27-CD27 ligand/CD70 interactions enhance alloantigen-induced proliferation and cytolytic activity in CD8+ lymphocytes. J Immunol. 1995;154(8):3686-3695.
  • 6. He LZ, Prostak N, Thomas LJ, et al. Agonist anti-human CD27 monoclonal antibody induces T cell activation and tumor immunity in human CD27-transgenic mice. J Immunol. 2013;191(8):4174-4183.

ICOS

  • Inducible T cell co-stimulator (ICOS) is an activating receptor expressed on the surface of activated cytotoxic T cells and other subsets of T cells1
  • ICOSL, the ligand for ICOS, is expressed on APCs. ICOS signaling through ICOSL leads to the expansion and survival of cytotoxic and memory T cells and cytokine secretion1-3
  • In preclinical studies, activation of ICOS signaling was required for T cell activation and function under both native conditions and during blockade of CTLA-44,5
References
  • 1. Hutloff A, Dittrich AM, Beier KC, et al. ICOS is an inducible T- cell co-stimulator structurally and functionally related to CD28. Nature. 1999; 397(6716):263-266.
  • 2. Burmeister Y, Lischke T, Dahler AC, et al. ICOS controls the pool size of effector-memory and regulatory T cells. J lmmunol. 2008; 180(2): 774-782.
  • 3. Yoshinaga SK, Whoriskey JS, Khare SD, et al. T- cell co-stimulation through B7RP-1 and ICOS. Nature. 1999; 402 (6763):827-832.
  • 4. Dong C, Juedes AE, Temann U-A, et al. ICOS co­stimulatory receptor is essential for T cell activation and function. Nature. 2001;409(6816):97-101-
  • 5. Fu T, He Q, Sharma P. The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti­CTLA-4 therapy. Cancer Res. 2011;71(16):5445-5 454.

KIR

  • Killer cell immunoglobulin-like receptors (KIRs) are immune checkpoint receptors expressed on the surface of natural killer (NK) cells. Data suggest they may also be expressed on cytotoxic T cells1,2
  • Inhibitory KIRs stop NK cells from killing normal cells, and tumor cells subvert this process to evade NK cell-mediated recognition and destruction1,3
  • In preclinical studies, blockade of inhibitory KIRs has been shown to help restore NK cell-mediated immune activity4,5
References
  • 1. Campbell KS, Purdy AK. Structure/function of human killer cell immunoglobulin-like receptors: lessons from polymorphisms, evolution, crystal structures and mutations. Immunology. 2011;132(3):315-325.
  • 2. Björkström NK, Béziat V, Cichocki F, et al. CD8 T cells express randomly selected KIRs with distinct specificities compared with NK cells. Blood. 2012;120(17):3455-3465.
  • 3. Carbone E, Neri P, Mesuraca M, et al. HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Blood. 2005;105:251-258.
  • 4. Waldhauer I, Steinle A. NK cells and cancer immunosurveillance. Oncogene. 2008;27(45):5932-5943.
  • 5. Romagné F, André P, Spee A, et al. Preclinical characterization of 1-7F9, a novel human anti–KIR receptor therapeutic antibody that augments natural killer–mediated killing of tumor cells. Blood. 2009;114(13):2667-2677.

SLAMF7

  • Signaling lymphocytic activation molecule family member 7 (SLAMF7) is an activating receptor expressed on the surface of virtually all natural killer (NK) cells and subsets of other immune cells1
  • Engagement of SLAMF7 activates NK cells, the rapid responders of the immune system and the body’s first line of defense against cancer2,3
  • Continuous activation of NK cells through pathways like SLAMF7 may stimulate cytotoxic T cells that initiate development of long-term immunity4,5
References
  • 1. Bouchon A, Cella M, Grierson HL, Cohen JI, Colonna M. Cutting edge: activation of NK cell-mediated cytotoxicity by a SAP-independent receptor of the CD2 Family. J Immunol. 2001;167(10):5517-5521.
  • 2. Cruz-Munoz ME, Dong Z, Shi X, Zhang S, Veillette A. Influence of CRACC, a SLAM family receptor coupled to the adaptor EAT-2, on natural killer cell function. Nat Immunol. 2009;10(3):297-305.
  • 3. Cheng M, Chen Y, Xiao W, Sun R, Tian Z. NK cell-based immunotherapy for malignant diseases. Cell Molec Immunol. 2013;10:230-252.
  • 4. Liu C, Lou Y, Lizée G, et al. Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice. J Clin Invest. 2008;118(3):1165-1175.
  • 5. Mocikat R, Braumüller H, Gumy A, et al. Natural killer cells activated by MHC Class ILow targets prime dendritic cells to induce protective CD8 T cell responses. Immunity. 2003;19(4):561-569.

CXCR4

  • CXCR4 is a G-protein-coupled receptor in the CXC chemokine receptor family found on the surface of T cells and other immune cells.1,2 Binding of CXCR4 to its ligand CXCL12 directs the migration and recruitment of immune cells3,4
  • The CXCR4 pathway is one of the most common chemokine receptors expressed in cancer, where it plays a key role in tumor-cell proliferation, migration, metastasis, invasion, and survival5-8
  • Preclinical data suggest that inhibition of the CXCR4 pathway promotes the accumulation of cytotoxic T cells and impairs tumor­-cell migration9
References
  • 1. Lee B, Sharron M, Montaner LJ, et al. Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages. Proc Natl Acad Sci U S A. 1999; 96(9):5215-5220.
  • 2. Loetscher M, Geiser T, O'Reilly T, et al. Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes. J Biol Chem. 1994; 269(1):232-237.
  • 3. Oberlin E, Amara A, Bachelerie F, et al. The CXC chemokine SDF-1 is the ligand for LESTR/ fusin and prevents infection by T cell-line-adapted HIV-1. Nature. 1996; 382(6594):833-835.
  • 4. Bleul CC, Fuhlbrigge RC, Casasnovas JM, et al. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med. 1996; 184(3): 1101-1109.
  • 5. Sun X, Cheng G, Hao M, et al. CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev. 2010; 29(4):709-722.
  • 6. Sehgal A, Keener C, Boynton AL, et al. CXCR-4, a chemokine receptor, is overexpressed in and required for proliferation of glioblastoma tumor cells. J Surg Oncol. 1998; 69(2): 99-104.
  • 7. Helbig C, Christopherson KW II, Bhat­ Nakshatri P, et al. NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem. 2003; 13;278(24):21631-21638.
  • 8. Chen Y, Stamatoyannopoulos G, Song CZ. Down-regulation of CXCR4 by inducible small interfering RNA inhibits breast cancer cell invasion in vitro. Cancer Res. 2003;63(16):4801-4804.
  • 9. Righi E, Kashiwagi S, Yuan J, et al. CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer. Cancer Res. 2011; 71(16):5522-5534.

BCR-ABL

  • BCR-ABL is a tyrosine kinase signaling fusion protein resulting from a genetic abnormality known as the Philadelphia chromosome1,2
  • BCR-ABL is constitutively active – it is continually sending signals that promote cell proliferation, resistance to apoptosis and premature release of myeloid cells from the bone marrow2-4
  • BCR-ABL is not found in normal cells, but is highly expressed in chronic myelogenous leukemia and acute lymphoblastic leukemia1,5
References
  • 1. Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973; 243(5405):290-293.
  • 2. Konopka JB, Watanabe SM, Witte ON. An alteration of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity. Cell. 1984; 37 (3):1035-1042.
  • 3. Bedi A, Zehnbauer BA, Barber JP, Sharkis SJ, Jones RJ. Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia. Blood. 1994; 83(9):2038-2044.
  • 4. Salgia R, Li J, Ewaniuk DS, Pear W, et al. BCR/ABL induces multiple abnormalities of cytoskeletal function. J Clin Invest. 1997; 100(1):46-57_
  • 5. Bloomfield CD, Lindquist LL, Arther D, et al. Chromosomal abnormalities in acute lymphoblastic leukemia. Cancer Res. 1981;41(11 Pt 2):4838-4843.

BET

  • The bromodomain and extra terminal domain (BET) family of proteins (BRD2, BRD3, BRD4, and BRDT) share a highly conserved structural motif that recruits transcription factors to activate gene transcription1-3
  • BET family members are responsible for the transcriptional regulation of various cancer-promoting oncogenes, such as C-MYC4,5
  • BET inhibition is associated with increased antitumor immune responses6,7
References
  • 1. Florence B, Faller DV. You BET-cha: a novel family of transcriptional regulators. Front Biosci. 2001; 6: 01008-01018.
  • 2. Rahman S, Sowa ME, Ottinger M, et al. The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. Mol Cell Biol. 2011; 31(13): 2641 – 2652.
  • 3. Dey A, Chitsaz F, Abbasi A, Misteli T, Ozato K. The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc Natl Acad Sci U S A. 2003; 100(15):8758-8763.
  • 4. Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-My c. Cell. 2011; 146(6):904-917.
  • 5. Hanson KO, Shichiri M, Follansbee MR, Sedivy JM. Effects of c-myc expression on cell cycle progression. Mol Cell Biol. 1994; 14(9):5748-5755.
  • 6. Zhu H. et al. 2016. Cell Reports. 16: 2829
  • 7. Kagoya et al 2016. J Clin Invest. 126(9):3479

PD-1

  • Programmed death-1 (PD-1) is an immune checkpoint receptor on cytotoxic T cells with two ligands, programmed death ligand-1 (PD-L1) and programmed death ligand-2 (PD-L2)1,2
  • Upregulation of the PD-1 receptor plays a key role in the debilitating process of T cell exhaustion3
  • Preclinical studies have shown that PD-1 blockade reinvigorates exhausted T cells and restores their cytotoxic function. Additionally, complete inhibition of PD-1 signaling through both PD-L1 and PD-L2 may reverse T cell exhaustion more effectively than inhibiting PD-L1 alone4,5
References
  • 1. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034.
  • 2. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261-268.
  • 3. Ahmadzadeh M, Johnson LA, Heemskerk B, et al. Tumor antigen–specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114(8):1537-1544.
  • 4. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439(7077):682-687.
  • 5. Hobo W, Maas F, Adisty N, et al. siRNA silencing of PD-L1 and PD L2 on dendritic cells augments expansion and function of minor histocompatibility antigen–specific CD8+ T cells. Blood. 2010;116(22):4501-4511.

CTLA-4

  • Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an immune checkpoint receptor and one of the most studied checkpoint pathways. It is expressed on the surface of T cells and regulatory T cells (Tregs)1-3
  • Tumor cells utilize the CTLA-4 pathway to suppress initiation of an immune response, decreasing T cell activation and ability to proliferate into memory T cells4
  • Preclinical data demonstrate that treatment with antibodies specific for CTLA-4 can restore an immune response through increased accumulation and survival of memory T cells and depletion of Tregs5,6
References
  • 1. Perkins D, Wang Z, Donovan C, et al. Regulation of CTLA-4 expression during T cell activation. J Immunol. 1996;156(11):4154-4159.
  • 2. Wing K, Onishi Y, Prieto-Martin P, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271-275.
  • 3. Le Mercier I, Lines JL, Noelle RJ. Beyond CTLA-4 and PD-1, the generation Z of negative checkpoint regulators. Front Immunol. 2015;6:418. doi: 10.3389/fimmu.2015.00418.
  • 4. Xia Y, Medeiros JL, Young KH. Immune checkpoint blockade: releasing the brake towards hematological malignancies. Blood Rev. 2015. pii: S0268-960X(15)00091-0. doi: 10.1016/j.blre.2015.11.003. [Epub ahead of print].
  • 5. Pedicord VA, Montalvo W, Leiner IM, Allison JP. Single dose of anti–CTLA-4 enhances CD8+ T cell memory formation, function, and maintenance. Proc Natl Acad Sci U S A. 2010; 109(1):266-271.
  • 6. Simpson TR, Li F, Montalvo-Ortiz W, et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma. J Exp Med. 2013;210(9):1695-1710.

TIM-3

  • T cell immunoglobulin mucin-3 (TIM-3) is an immune checkpoint receptor expressed on the surface of cytotoxic T cells, regulatory T cells (Tregs) and NK-cells1-4
  • Increasing expression of TIM-3 on cytotoxic T cells and the interaction of TIM-3 on NK-cells with the ligand Galectin-9 are associated with T cell and NK-cell exhaustion and dysfunction, respectively. In addition, Tregs expressing TIM-3 show enhanced immunosuppressive function. TIM-3 signaling can also suppress the immune function of monocytes5-8
  • Preclinical data suggest that blockade of TIM-3 can restore cytotoxic T cell proliferation and function3,6,9
References
  • 1. Anderson AC. Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer lmmunol Res. 2014; 2(5):393-398.
  • 2. Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: co­inhibitory receptors with specialized functions in immune regulation. Immunity. 2016; 44(5):989-1004.
  • 3. Sakuishi K, Ngiow SF, Sullivan JM, et al. TIM3+FOXP3+regulatory T cells are tissue-specific promoters of T- cell dysfunction in cancer. Oncoimmunology. 2013; 2(4):e23849. doi:10.4161/onci.23849.
  • 4. Monney L, Sabatos CA, Gaglia JL, et al.Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmunedisease. Nature. 2002; 415(6871):536-541.
  • 5. da Silva IP, Gallois A, Jimenez-Baranda S, et al. Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade. Cancer lmmunol Res. 2014; 2(5):410-422.
  • 6. Fourcade J, Sun Z, Benallaoua M, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CDS+ T cell dysfunction in melanoma patients. J Exp Med. 2010; 207(10):2175-2186.
  • 7. Gautron AS, Dominguez-Villar M, de Marcken M, Hafler DA. Enhanced suppressor function of TIM-3+ FoxP3+ regulatory T cells. Eur J lmmunol. 2014; 44(9):2703-2711.
  • 8. Zhang Y, Ma CJ, Wang JM, et al. Tim-3 regulates pro- and anti-inflammatory cytokine expression in human CD14+ monocytes. J Leukoc Biol. 2012; 91(2):189- 196.
  • 9. Sakuishi K, Apetoh L, Sillivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti- tumor immunity. J Exp Med. 2010; 207(10): 2187- 2194.

TIGIT

  • TIGIT is an immune checkpoint receptor expressed on immune cells such as cytotoxic T cells
  • TIGIT has two ligands, CD155 and CD112. CD155 and CD112 are also ligands for CD226
  • CD226 competes with TIGIT to stimulate T cell activation. However ligand interaction with TIGIT overpowers CD226 to suppress immune activation
  • Tumor cells upregulate CD155 and CD112 to avoid immune-mediated destruction. Inhibition of TIGIT can increase T cell proliferation and function
References
  • 1. Bottino C, Castriconi R, Pende D, et al. Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med. 2003;198(4):557-567.
  • 2. Chauvin JM, Pagliano O, Fourcade J, et al. TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J Clin Invest. 2015;125(5):2046-2058
  • 3. Goding SR, Wilson KA, Xie Y, et al. Restoring immune function of tumor-specific CD4+ T cells during recurrence of melanoma. J Immunol. 2013;190(9):4899-4909.
  • 4. Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell. 2014;26(6):923-937
  • 5. Joller N, Hafler JP, Brynedal B, et al. Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol. 2011;186(3):1338-1342.
  • 6. Lozano E, Dominguez-Villar M, Kuchroo V, Hafler DA. The TIGIT/CD226 axis regulates human T cell function. J Immunol. 2012;188(8):3869-3875.
  • 7. Stanietsky N, Simic H, Arapovic J, et al. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci USA. 2009;106(42): 17858-17863.
  • 8. Yu X, Harden K, Gonzalez LC, et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol. 2009;10(1):48-57.

LAG 3

  • Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor protein found on the cell surface of effector T cells and regulatory T cells (Tregs) and functions to control T cell response, activation and growth1
  • After a T cell is activated to kill its target cell, LAG-3 expression is increased to turn off the immune response2
  • However, in certain situations where T cells experience prolonged exposure to an antigen, the T cells become desensitized and lose their ability to activate and multiply in the presence of the antigen.3 The desensitized T cell will also progressively fail to produce cytokines (proteins that assist in the immune response) and kill the target cells.3 This process is called T cell exhaustion and is associated with an increased expression of inhibitory receptors such as LAG-33
  • Preclinical studies suggest that inhibiting LAG-3 allows T cells to regain their cytotoxic function and potentially affect tumor growth 4
References
  • 1. Nicholas Durham, et al. Lymphocyte Activation Gene 3 (LAG-3) modulates the Ability of CD4 T- cells to Be Suppressed in Vivo. PLoS ONE. November 2014. DOI: 10.1371/journal.pone.0109080.
  • 2. Workman, C. J., et al. Phenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG3) Eur. J. Immunol. 32, 2255–2263 (2002).
  • 3. Wherry, E. J. T cell exhaustion. Nature Immunol. 12, 492–499 (2011).
  • 4. Grosso JF., Kelleher CC, Harris TJ, et al. LAG-3 regulates CDS+ T cell accumulation and effector function in murine self and tumor-tolerance systems. J Clin Invest. 2007;117(11):3383-3392.

CCR2/5

  • CCR2 and CCR5, expressed on the surface of T cells, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) are chemokine receptors that play a role in trafficking of immunosuppressive cells to sites of inflammation and tumors1-8
  • The ligands for CCR2 and CCR5 (CCL2 and CCL5, respectively), are expressed by stromal cells. Signaling through these receptor/ligand interactions promotes the infiltration of MDSCs, TAMs and Tregs to the tumor microenvironment and the differentiation of TAMs, which can suppress cytotoxic T cell proliferation and function1-5,8,10,11
  • Preclinical data suggest that depletion or blockade of CCR2 and CCR5 individually, or in combination, has been shown to decrease the infiltration of MDSCs, TAMs and Tregs to the tumor microenvironment1,5,12
References
  • 1. Chang LY, Lin YC, Mahalingam J, et al. Tumor-derived chemokine CCL5 enhances TGF β mediated killing of CD8(+) T cells in colon cancer by T-regulatory cells. Cancer Res. 2012; 72(5): 1092-1102.
  • 2. Tan MC, Goedegebuure PS, Belt BA, et al. Disruption of CCR5- dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J lmmunol. 2009; 182(3):1746-1755.
  • 3. Huang B, Lei S, Zhao J, et al. CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers. Cancer Left. 2007; 252(1):86-92.
  • 4. Lesokhn AM, Hohl TM, Kitano S, el al. Monocytic CCR2(+) myeloid­ derived suppressor cells promote immune escape by limiting activated CD8 T- cell infiltration into the tumor microenvironment. Cancer Res. 2012:72 (4):876-886.
  • 5. Sanford DE, Bella BA, Panni RZ. et al. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin Cancer Res. 2013; 19(13): 3404- 3415.
  • 6. Lim HW, Lee J, Hillsamer P, Kim CH. Human Th17 cells share major trafficking receptors with both polarized effector T cells and FOXP3+regulatory T cells. J lmmunol. 2008; 180(1):122-129.
  • 7. Sica A, Saccani A. Bottazzi B, et al. Defective expression of the monocyte chemotactic protein-1 receptor CCR2 in macrophages associated with human ovarian carcinoma. J lmmunol. 2000; 164(2): 733-738.
  • 8. Weitzenfeld P, Ben-Baruch A. The chemokine system, and its CCRS and CXCR4 receptors, as potential targets for personalized therapy in cancer. Cancer Lett. 2014; 352(1):36-53.
  • 9. Lim SY, Yuzhalin AE, Gordon-Weeks AN, Muschel RJ. Targeting the CCL2-CCR2 signaling axis in cancer metastasis. Oncotarget. 2016; 7 (19): 28697-28710.
  • 10. Loberg RD, Ying C, Craig M, Yan L, Snyder LA, Pienta KJ. CCL2 is an important mediator of prostate cancer growth in vivo through the regulation of macrophage infiltration. Neoplasia. 2007; 9(7):556-562.
  • 11. Roca H, Varsos ZS, Sud S, Craig MJ, Ying C, Pienta KJ. CCL2 and interleukin-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization. J Biol Chem. 2009; 284(49):34342-34354.
  • 12. Lefebvre E, Moyle G, Reshef R, et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PloS One. 2016; 11(6):e0158156. doi:1.0137/1journal.po.O1e58156

IL-8

  • Interleukin8 (IL-8) is a chemokine produced by macrophages and monocytes that binds to the G protein-coupled receptors CXCR1 and CXCR2 on the surface of myeloid-derived suppressor cells (MDSCs)1-3
  • Expressed by a wide range of solid tumors and stromal cells, IL-8 can promote MDSC migration to the tumor microenvironment, leading to suppression of the antitumor immune response and increased expansion of the stromal barrier1,3-7
  • Preclinical data suggests that blockade of tumor-derived IL-8 reduces recruitment of CXCR1- and CXCR2-expressing MDSCs to the stroma barrier and tumor microenvironment. IL-8 is associated with poor prognosis and resistance to immunotherapy3
References
  • 1. David JM, Dominguez C, Hamilton DH. Palena C. The lL-8/lL-8R axis: a double agent in tumor immune resistance. Vaccines (Basel). 2016; 4(3). pii:E22. doi:10.3390/vaccines4030022.
  • 2. Waugh DJJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res. 2008; 14 (21):6735-6741.
  • 3. Alfaro C, Teijeira A, Onate C, et al. Tumor-produced interleukin-8 attracts human myeloid-derived suppressor cells and elicits extrusion of neutrophil extracellular traps (NETs). Clin Cancer Res. 2016; 22 (15):3924-3936.
  • 4. Katanov C, Lerrer S, Liubomirski Y, et al. Regulation of the inflammatory profile of stromal cells in human breast cancer: prominent roles for TNF-α and the NF-KB pathway. Stem Cell Res Ther. 2015; 6(87). doi:10.1186/s13287-015-0080-.7
  • 5. Subramaniam KS, Tham ST, Mohamed Z, Woo YL, Mat Adenan NA, Chung I. Cancer-associated fibroblasts promote proliferation of endometrial cancer cells. PLoS One. 2013; 8 (7):e68923. doi:10_1371/journal.pone.0068923.
  • 6. Sanmamed MF, Carranza-Rua O, Alfaro C, et al. Serum interleukin-8 reflects tumor burden and treatment response across malignancies of multiple tissue origins. Clin Cancer Res. 2014; 20(22):5697-5707.
  • 7. Asfaha S, Dubeykovskiy AN, Tomita H, et al. Mice that express human interleukin-8 have increased mobilization of immature myeloid cells, which exacerbates inflammation and accelerates colon carcinogenesis. Gastroenterology. 2013; 144(1):155-166.

NLRP3

  • NLRP3 is involved in the regulation of the innate immune response 1-3
  • NLRP3 can be activated through the release of signaling molecules (ATP/DAMPs) from treatment or immune-mediated tumor cell death1-3
  • Inhibiting NLRP3 has the potential to activate an initial innate immune response by producing IL-1ß and IL-18 by priming, expanding and activating CD8+ T cells and NK-cells. In turn, this may promote tumor inflammation and enhance antitumor function1,4,5
References
  • 1. Chow MT et al. Semin Cancer Biol. 2012;22(1):23-32.
  • 2. Dupaul-Chicoine 3 et al. Immunity. 2015;43(4):751-763.
  • 3. Ghiringhelli F et al. Nat Med. 2009;15(10)1170-1178
  • 4. Embry et al. Sci Signal. 2011;4(171):ra28.
  • 5. Sharma et al. J Cell Biol. 2016;213(6):617-629.
  • 6. IFM Therapeutics Pipeline. Accessed September 21, 2017.

STING

  • The STING pathway is activated by cytosolic DNA released by tumor cell death1,2
  • STING activation induces the transcription of IFN and other cytokines1,2
  • Preclinical studies have shown that activating the STING pathway, in combination with other complementary immune pathways, may lead to increased CD8+ T cell infiltration and an inflamed tumor microenvironment1-4
References
  • 1. Corrales L, Gajewski TF. Clin Cancer Res. 2015;21(21):4774-4779.
  • 2. Corrales Let al. J Clin Invest 2016:126(7):2404 -2411.
  • 3. Fu J et al. Sci Transl Med. 2015:7(283):283ra52.
  • 4. Woo et al. Trends Immunol. 2015;36(4):250-256.
  • 5. IFM Therapeutics Pipeline. Accessed September 21, 2017.

Viruses

  • Oncolytic viruses preferentially target and replicate within tumor cells and can be "unarmed" or "armed"
    - "Unarmed" viruses lyse host cells, which can lead to the release of tumor antigens and cytotoxic T cell activation1-3
    - "Armed" viruses not only lyse host cells, but are also engineered to express proteins that can further modulate the antitumor immune response3-5
  • Once internalized by the tumor cell, oncolytic viruses replicate and, if "armed," can induce the expression of immunomodulatory proteins. Lysis of the host cell releases tumor antigens and new viruses into the tumor microenvironment1,3
  • Preclinical data suggest that oncolytic viruses promote cytotoxic T cell activation, which can be further enhanced by immunomodulatory proteins expressed from "armed" viruses6-9
References
  • 1. Babiker HM, Riaz IB, Husnain M, Borad MJ. Oncolytic virotherapy including Rigvir and standard therapies in malignant melanoma. Oncolylic Virother. 2017; 6:11-18.
  • 2. Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses : a new class of immunotherapy drugs. Nat Rev Drug Discov. 2015; 14(9):642-662.
  • 3. Seymour LW, Fisher KD. Oncolytic viruses; finally delivering. Br J Cancer. 2016; 114(4):357-361.
  • 4. Aurelian L. Oncolytic viruses as immunotherapy: progress and remaining challenges. Onco Targets Ther. 2016; 9:2627-2637.
  • 5. Uusi-Kerttula H, Hulin-Curtis S, Davies J, Parker AL. Oncolytic adenovirus: strategies and insights for vector design and immuno-oncolytic applications. Viruses. 2015; 7(11):6009-6042.
  • 6. Li X, Wang P, Li H, et al. The efficacy of oncolytic adenovirus is mediated by T- cell responses against virus and tumor in Syrian hamster model. Clin Cancer Res. 2017; 23(1):239-249.
  • 7. Champion B, Rasiah N, Illingworth S, et al. Developing tumor-localized combination immunotherapies. Poster presentation at AACR 2016.
  • 8. Tuve S, Liu Y, Tragoolpua K, et al. In situ adenovirus vaccination engages T effector cells against cancer. Vaccine. 2009; 27(31): 4225-4239.
  • 9. Kim SK, Kim-Schulze S, Kim OW, Kaufman HL. Host lymphodepletion enhances the therapeutic activity of an oncolytic vaccinia virus expressing 4-1BB ligand. Cancer Res. 2009;69(21):8516- 8525.

IDO

  • Indoleamine-2,3-dioxygenase-1 (IDO) is an intracellular enzyme that initiates the breakdown of tryptophan in the tumor microenvironment1,2
  • Tryptophan metabolism by IDO regulates T cell immune responses. Tumor cells hijack this immune suppressive process by upregulating IDO activity, starving cytotoxic T cells and triggering regulatory T cell development3-7
  • Based on preclinical studies, blockade of IDO can reduce the number of regulatory T cells and restore cytotoxic T cell function6,8
References
  • 1. Mellor AL, Munn DH. Tryptophan catabolism and T cell tolerance: immunosuppression by starvation? Immunol Today. 1999;20(10):469-473.
  • 2. Munn DH, Sharma MD, Lee JR, et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science. 2002;297(5588):1867-1870.
  • 3. Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med. 1999;189(9):1363-1372.
  • 4. Löb S, Königsrainer A, Zieker D, et al. IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism. Cancer Immunol Immunother. 2009;58(1):153-157.
  • 5. Liu P, Xie BL, Cai SH, et al. Expression of indoleamine 2,3-dioxygenase in nasopharyngeal carcinoma impairs the cytolytic function of peripheral blood lymphocytes. BMC Cancer. 2009;9:416. doi: 10.1186/1471-2407-9-416.
  • 6. Wainwright DA, Balyasnikova IV, Chang AL, et al. IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin Cancer Res. 2012;18(22):6110-6121.
  • 7. Fallarino F, Grohmann U, You S, et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor ζ-chain and induce a regulatory phenotype in naive T cells. J Immunol. 2006;176(11):6752-6761.
  • 8. Uyttenhove C, Pilotte L, Théate I, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003;9(10):1269-1274.

CCR4

  • CCR4 is a chemokine receptor found on the surface of regulatory T cells (Tregs) and other immune cell subsets1-5
  • Ligands for CCR4, such as CCL17 and CCL22, can be found within the tumor microenvironment, where they recruit Tregs capable of inhibiting cytotoxic T cell function6,7
  • Preclinical evidence suggests that CCR4 inhibition abrogates Treg migration and promotes T cell expansion8
References
  • 1. Imai T, Baba M, Nishimura M, et al. The T cell-directed CC chemokine TARC is a highly specific biological ligand for CC chemokine receptor 4. J Biol Chem. 1997; 272(23):15036-15042.
  • 2. Imai T. Chantry D, Raport CJ, et al. Macrophage-derived chemokine is a functional ligand for the CC chemokine receptor 4. J Biol Chem. 1998; 273(3):1764-1768.
  • 3. lnngjerdingen M, Damaj ,B Maghazachi AA. Human NK cells express CC chemokine receptors 4 and 8 and respond to thymus and activation­ regulated chemokine, macrophage-derived chemokine, and 1-309. J Immunol. 2000; 164(8): 4048-4054.
  • 4. lellem A, Mariani M, Lang R, et al. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4+CD25+ regulatory T cells. J Exp Med. 2001; 194(6):847-853.
  • 5. Yoshie O, Matsushima K. CCR4 and its ligands: from bench to bedside. Int lmmunol. 2014; 27(1): 11-20.
  • 6. 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.
  • 7. Mizukami Y, Kono K, Kawaguchi Y, et al. Int J Cancer. 2008; 122(10):2286-2293.
  • 8. Bayry J, Tchilian EZ, Davies MN , et al. In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination. Proc Natl Acad Sci U S A. 2008; 105 (29):10221-10226.

CD73

  • CD73 is a cell-surface enzyme on regulatory T cells, where it is a critical checkpoint in the conversion of immune-activating ATP into immunosuppressive adenosine1
  • Tumor cells express CD73 and release adenosine into the tumor microenvironment, inhibiting the antitumor immune response1-4
  • Preclinical research has identified tumor-derived CD73 as a contributor to immune escape in cancer, and inhibition of CD73 activity can stimulate T cell activity5
References
  • 1. Kobie JJ, Shah PR, Yang L, Rebhahn JA, Fowell DJ, Mosmann TR. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5’-adenosine monophosphate to adenosine. J Immunol. 2006;177(10):6780-6786.
  • 2. Häusler SF, del Barrio IM, Strochschein J, et al. Ectonucleotidases CD39 and CD73 on OvCA cells are potent adenosine-generating enzymes responsible for adenosine receptor 2A-dependent suppression of T cell function and NK cell cytotoxicity. Cancer Immunol Immunother. 2011;60(10):1405-1418.
  • 3. Serra S, Horenstein AL, Vaisitti T, et al. CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death. Blood. 2011;118(23):6141-6152.
  • 4. Ohta A, Gorelik E, Prasad SJ, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci U S A. 2006;103(35):13132-13137.
  • 5. Stagg J, Divisekera U, McLaughlin N, et al. Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc Natl Acad Sci U S A. 2010;107(4):1547-1552

CTLA-4-NF

  • Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an immune checkpoint receptor and one of the most studied checkpoint pathways. It is expressed on the surface of T cells and regulatory T cells (Tregs)1-3
  • Tumor cells utilize the CTLA-4 pathway to suppress initiation of an immune response, decreasing T cell activation and ability to proliferate into memory T cells4
  • Preclinical data demonstrate that treatment with antibodies specific for CTLA-4 can restore an immune response through increased accumulation and survival of memory T cells and depletion of Tregs5,6
  • One second-generation approach for CTLA-4 antibodies is to design a non-fucosylated Fc region that can improve binding by accessory immune cells to enhance Treg depletion7,8
References
  • 1. Perkins D, Wang Z, Donovan C, et al. Regulation of CTLA-4 expression during T cell activation. J lmmunol.1996;156(11):4154-4159.
  • 2. Wing K. Onishi Y, Prieto-Martin P, et al. CTLA- 4 control over Foxp3+ regulatory T cell function. Science. 2008 ;322 (5899):27 1-275.
  • 3. Le Mercier I, Lines JL, Noelle RJ. Beyond CTLA-4 and P0-1, the generation Z of negative checkpoint regulators. Front lmmunol. 2015;6:418. doi:10.3389/fimmu.2015.00418.
  • 4. Xia Y, Medeiros LJ. Young KH. Immune checkpoint blockade: releasing the brake towards hematological malignancies. Blood Rev. 2016;30(3):189-200.
  • 5. Pedicord VA. Montalvo W, Leiner IM, Allison JP. Single dose of anti- CTLA- 4 enhances CD8+ T- cell memory formation, function, and maintenance. Proc Natl Acad Sci USA. 2011;108(1):266-271-
  • 6. Simpson TR, Li F, Montalvo-Ortiz W, et al. Fe­ dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti- CTLA-4 therapy against melanoma. J Exp Med. 2013;210 (9):1695-1710.
  • 7. Chiang AWT, Li S, Spahn PN, et al. Modulating carbohydrate - protein interactions through glycoengineering of monoclonal antibodies to impact cancer physiology. Curr Opin Struct Biol. 2016;40:104-111.
  • 8. Satoh M, Iida S, Shitara K. Non-fucosylated therapeutic antibodies as next-generation therapeutic antibodies. Exp Opin Biol Ther. 2006;6 (11):1161-1173.

TGFβ

  • Transforming growth factor beta receptor (TGFβ), a receptor for the anti-inflammatory cytokine transforming growth factor (TGF) beta, consists of two receptor dimers, TGF beta receptor 1 and TGF beta receptor 2, which are expressed on the surface of various normal and tumor cells1,2
  • TGFβ signaling in the tumor microenvironment can promote immunosuppression altering the balance of regulatory T cells (Tregs) to tumor-infiltrating T cells3,4
  • Preclinical data suggest that inhibiting TGFβ activity can increase the activity of cytotoxic T cells and natural killer cells, while reducing the number of immunosuppressive Tregs5
References
  • 1. Yamashita H, ten Dijke P, Franzen P, Miyazono K, Heldin C- H. Formation of hetero-oligomeric complexes of type I and type II receptors for transforming growth factor-β. J Biol Chem. 1994;269 (31):20172-20178.
  • 2. Massague J, Like B. Cellular receptors for type β transforming growth factor. J Biol Chem. 1984; 260(5):2636-2645.
  • 3. Neuzillet C, Tijeras-Raballand A, Cohen R, et al. Targeting the TGFβ pathway for cancer therapy. Pharmacol Ther. 2015; 147:22-31.
  • 4. Pickup M, Novitskiy S, Moses HL. The roles of TGFβ in the tumour microenvironment. Nat Rev Cancer. 2013; 13(11): 788-799.
  • 5. Zhong Z, Carroll KD, Policarpio D, et al. Anti-transforming growth factor β receptor II antibody has therapeutic efficacy against primary tumor growth and metastasis through multieffects on cancer, stroma, and immune cells. Clin Cancer Res. 2010; 16(4):1191- 1205.

CSF1R

  • Colony-stimulating factor 1 receptor (CSF1R) is a cell-surface receptor expressed by macrophages and other cells of the myeloid lineage1
  • Mouse models have shown that tumor cells use the CSF1R pathway to stimulate the development and survival of tumor-associated macrophages (TAMs), which promote cancer survival and drive immunosuppression2-4
  • In preclinical studies, blockade of CSF1R—depriving CSF1 of its target receptor—resulted in depletion of TAMs and improved T cell response5-6
References
  • 1. Stanley ER, Chitu V. CSF-1 receptor signaling in myeloid cells. Cold Spring Harb Perspect Biol. 2014;6:a021857.
  • 2. Zhu Y, Knolhoff BL, Meyer MA, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res.2014;74(18):5057-5069.
  • 3. Richardsen E, Uglehus RD, Johnsen SH, Busnd LT. Macrophage-colony stimulating factor (CSF1) predicts breast cancer progression and mortality. Anticancer Res. 2015;35(2):865-874.
  • 4. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41(1):49-61.
  • 5. Ries CH, Cannarile MA, Hoves S, et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell. 2014;25:846-859.
  • 6. Mitchem JB, Brennan DJ, Knolhoff BL, et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 2013;73:1128-1141.