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Cancer Immunology

Learn more about the cancer-immunity cycle and immune checkpoints.

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Cancer-Immunity Cycle
Immune Checkpoints
PD-L1 Pathway
TIGIT Pathway
Abbreviations

Cancer-Immunity Cycle

The genetic and cellular alterations that characterize cancer cells can be recognized by the immune system as foreign, resulting in T cells being able to kill cancer cells.1 The entire process by which the immune system recognizes, targets, and kills cancer cells is described by the cancer-immunity cycle.

The Cancer-Immunity Cycle Is Comprised of a Series of 7 Rate-Limiting Steps Governing the Anti-Tumor Response1

1 Release of cancer cell antigens: Tumor antigens are released upon oncogenesis and captured by dendritic cells for processing.

2 Cancer antigen presentation: Antigens are transported to the lymph nodes for presentation to T cells, and the immune response is initiated.

3 Priming and activation: Dendritic cells present antigens to T cells and an activation program is initiated, priming T cells to attack the tumor. T cell activation is regulated by immune checkpoints.

4 Trafficking of T cells to tumors: Activated T cells travel in the bloodstream from the lymph nodes to the tumor site.

5 Infiltration of T cells into tumors: Activated T cells infiltrate the tumor microenvironment via blood vessels in a process that involves rolling and tethering along the endothelium.

6 Recognition of cancer cells by T cells: Activated T cells recognize tumor cells through binding of the T cell receptors to its cognate, MHC class I–presented antigen.

7 Killing of cancer cells: Killing of cancer cells releases additional antigens, reinitiating the cancer-immunity cycle.

References

  1. Chen DS, Mellman I. Immunity. 2013;39(1):1-10. doi:10.1016/​j.immuni.2013.07.012

Immune Checkpoints

Immune checkpoints are regulatory pathways in the immune system that ensure an appropriate duration and amplitude of immune response, and are crucial for1-3:

Modulating immune responses

Preventing autoimmunity

Minimizing collateral damage

Tumors can inhibit the anticancer response by disrupting the balance governing the steps of the cancer-immunity cycle through a specific pathway or a combination of pathways.1,2 Therefore, the anticancer immune response potentially can be enhanced by:

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Activating stimulatory checkpoints that promote the immune response

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Blocking inhibitory checkpoints that downregulate the immune response, such as the PD-L1 pathway

Genentech is continuing to advance the understanding of cancer immunotherapy by researching pathways that can be targeted simultaneously with the PD-L1/PD-1 pathway to address various immune escape mechanisms in cancer

References

  1. Chen DS, Mellman I. Nature. 2017;541(7637):321-330. doi:10.1038/​nature21349
  2. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264. doi:10.1038/​nrc3239

PD-L1 Pathway

As a key immunosuppressive driver, the PD-L1 pathway is an important target that may help invigorate antitumor T cell activity in the tumor microenvironment.1,2

PD-L1 binds to two receptors: B7.1 and PD-1.1-3 When bound to their receptors, cytotoxic T cell activity is downregulated, thereby protecting normal cells from autoimmunity.

  • PD-L1 is broadly expressed in multiple tissue types, including hematopoietic, endothelial, and epithelial cells
  • B7.1 is primarily expressed on dendritic cells and to a lesser extent on T cells
  • PD-1 is expressed primarily on activated T cells

The PD-L1 Pathway Downregulates the Anticancer Immune Response at Two Different Levels4

In cancer, the PD-L1 pathway downregulates the anticancer immune response by inhibiting cytotoxic T cell activity in the tumor microenvironment and preventing the priming and activation of new T cells in the lymph node.4

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3 Priming and activation: PD-L1 expression prevents T cell priming and activation in the lymph node.

7 Killing of cancer cells: PD-L1 expression leads to the inhibition of anti-cancer T cell activity in the tumor microenvironment.

Targeting the PD-L1 Pathway2,3

Binding of the ligand PD-L1 to its inhibitory receptors PD-1 and B7.1 on T cells can suppress cytotoxic T cell activity

PD-L1 inhibition prevents T cell deactivation

Reinvigorated T cells may restore immune function

Cancers may use multiple immune escape mechanisms.4 Targeting PD-L1 simultaneously with other pathways may help restore the cancer-immunity cycle

References

  1. Keir ME, et al. Annu Rev Immunol. 2008;26:677-704. doi:10.1146/​annurev.immunol.26.021607.090331
  2. Chen DS, et al. Clin Cancer Res. 2012;18(24):6580-6587. doi:10.1158/​1078-0432.CCR-12-1362
  3. Butte MJ, et al. Immunity. 2007;27(1):111-112. doi:10.1016/​j.immuni.2007.05.016
  4. Chen DS, Mellman I. Immunity. 2013;39(1):1-10. doi:10.1016/​j.immuni.2013.07.012

TIGIT Pathway

TIGIT is a novel checkpoint inhibitor that is expressed on multiple immune cells, including CD8+, CD4+, regulatory T cells, and NK cells.1,2 TIGIT has a co-inhibitory receptor role and counterbalances the co-stimulatory function of CD226.

In normal circumstances, after binding with PVR, CD226 turns on the immune response by activating T cells and NK cells.1-3

  • TIGIT binds with high affinity to PVR and competes with CD226
  • After binding with PVR, TIGIT turns off the immune response by inhibiting T cell activation3

TIGIT Inhibits the Immune Response via 3 Key Mechanisms1-7

TIGIT inhibits T and NK cells by binding to PVR3

Down-modulates APCs to enhance production of immunosuppressive IL-101,3,4

TIGIT inhibits positive signaling by the co-stimulatory CD226 receptor by binding to PVR at a higher affinity1-7

TIGIT in the Cancer-Immunity Cycle

In some cancers, multiple immune checkpoints work together to modulate the immune response and effectively suppress an anticancer immune-mediated response. The TIGIT pathway has a distinct but complementary effect to the PD-1/PD-L1 pathway on the immune response.4

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3 Priming and activation: TIGIT and PD-1 inhibitory pathways converge to inactivate CD226, a key activating receptor required for full CD8+ T cell effector function.2

7 Killing of cancer cells: PD-1 mediates dephosphorylation of both CD28 and CD226, thereby suppresses T cell function.2

Optimal activation of CD226 may require coordinated inhibition of both TIGIT and PD-1, which may lead to reprogramming of suppressive mechanisms in the tumor microenvironment to enable activation of CD8+ T cells2,4

View the above information on the TIGIT pathway in the format of a downloadable PDF.

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References

  1. Manieri NA, et al. Trends Immunol. 2017;38(1):20-28. doi:10.1016/​j.it.2016.10.002
  2. Chiang EY, Mellman I. J Immunother Cancer. 2022; 10(4):e004711. doi:10.1136/​jitc-2022-004711
  3. Yu X, et al. Nat Immunol. 2009;10(1):48-57. doi:10.1038/ni.1674
  4. Banta KL, et al. Immunity. 2022;55(3):512-526.e9. doi:10.1016/​j.immuni.2022.02.005
  5. Dardalhon V, et al. J Immunol. 2005;175(3):1558-1565. doi:10.4049/​jimmunol.175.3.1558
  6. Carlsten M, et al. Cancer Res. 2007;67(3):1317-1325. doi:10.1158/0008-5472.CAN-06-2264
  7. Levin SD, et al. Eur J Immunol. 2011;41(4):902-915. doi:10.1002/​eji.201041136

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  • AAAAI
    American Academy of Allergy Asthma & Immunology

  • ABC
    activated B-cell–like subtype

  • AE
    Adverse event

  • Ang2
    Angiopoietin-2

  • ARR
    Annualized Relapse Rate

  • ART
    Assisted Reproductive Technology

  • ASTCT
    American Society for Transplantation and Cellular Therapy

  • ATG
    Anti-thymocyte globulin

  • CAR
    Chimeric antigen receptor

  • CD3
    Cluster of differentiation 3

  • CD4
    Cluster of differentiation 4

  • CD8
    Cluster of differentiation 8

  • CD19
    Cluster of differentiation 19

  • CD20
    Cluster of differentiation 20

  • CD226
    Cluster of differentiation 226

  • CDC
    Centers for Disease Control and Prevention

  • CI
    Confidence Interval

  • COVID-19
    Coronavirus disease of 2019

  • CPAP
    Continuous positive airway pressure

  • CR
    Complete response

  • CRP
    C-reactive protein

  • CRS
    Cytokine release syndrome

  • CT
    Computed tomography

  • CTCAE
    Common Terminology Criteria for Adverse Events

  • DIC
    Disseminated intravascular coagulation

  • DLBCL
    Diffuse large B-cell lymphoma

  • DMT
    Disease-modifying therapy

  • DMT
    Disease-modifying treatment

  • DoCR
    Duration of complete response

  • DoR
    Duration of response

  • DBPCFC
    Double-blind, placebo-controlled food challenge

  • ECOG PS
    Eastern Cooperative Oncology Group performance status

  • ECTRIMS
    European Committee for Treatment and Research in Multiple Sclerosis

  • EDSS
    Expanded Disability Status Scale

  • EFSefficacy
    event-free survival for efficacy causes (time from randomization to the earliest occurrence of disease progression/relapse, death due to any cause, initiation of any non-protocol specified anti-lymphoma treatment, or biopsy-confirmed residual disease after treatment completion)

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    European Medicines Association

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    end of treatment

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    FDA Adverse Event Reporting System

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    Food and Drug Administration

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    US Food and Drug Administration

  • FL
    Follicular lymphoma

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    germinal-center B-cell–like subtype

  • HCP
    Health Care Provider

  • HGBCL
    High-grade B-cell lymphoma

  • HGBL
    high-grade B-cell lymphoma

  • HHV8
    human herpesvirus 8

  • HLH
    Hemophagocytic lymphohistiocytosis

  • HR
    hazard ratio

  • ICANS
    Immune effector cell-associated neurotoxicity syndrome

  • ICU
    Intensive care unit

  • Ig
    Immunoglobulin

  • IgE
    Immunoglobulin E

  • IgG1
    Immunoglobulin G1

  • INR
    International normalized ratio

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    International Prognostic Index

  • IRC
    Independent Review Committee

  • IRR
    Infusion-related reaction

  • ITIM
    Immunoreceptor tyrosine-based inhibitory motif

  • ITT
    intention-to-treat

  • LLN
    Lower limit of normal

  • LMP
    last menstrual cycle

  • LMP
    Last menstrual period

  • MAS
    Macrophage activation syndrome

  • MCA
    Major congenital anomalies

  • MHC
    Major histocompatibility complex

  • MS
    Multiple sclerosis

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    Memorial Sloan Kettering Cancer Center

  • NK
    Natural killer

  • NO
    Nitric oxide

  • NOS
    Not otherwise specified

  • OB/Gyn
    Obstetrics and Gynecology

  • OCR
    OCREVUS (ocrelizumab)

  • OR
    Odds ratio

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    Objective response rate

  • OS
    overall survival

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    Programmed cell death protein 1

  • PD-L1
    Programmed death-ligand 1

  • PET
    Positron emission tomography

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    Progression-free survival

  • PMBCL
    Primary mediastinal B-cell lymphoma

  • PML
    progressive multifocal leukoencephalopathy

  • Pola-R-CHP
    polatuzumab plus rituximab, cyclophosphamide, doxorubicin, prednisone

  • PPMS
    Primary progressive multiple sclerosis

  • PTT
    Partial thromboplastin time

  • PVR
    Poliovirus receptor

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    rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone

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    rituximab plus cyclophosphamide, doxorubicin, prednisone

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    Relative infant dose

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    Relapsing multiple sclerosis

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    Relapsing-remitting multiple sclerosis

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    Serious adverse event

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    Trimester

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    T-cell receptor

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    T cell immunoreceptor with Ig and ITIM domains

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    University of California San Francisco

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    United States Prescribing Information

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    Upper respiratory tract infection

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    Urinary tract infection

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    von Wilebrand factor

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    National Institutes of Health