There are many natural immune effector mechanisms for tumor detection and elimination.1 Regular function of these mechanisms helps prevent tumor growth and metastasis.1,2 By the time a tumor has developed, mechanisms are established that allow that tumor to avoid destruction by the immune system.

The discovery and development of immuno-oncology therapy in recent years represents a milestone in the treatment of cancer. Unlike traditional therapies that focus on attacking the tumor cells themselves, immuno-oncology focuses on mobilizing the patient's own immune cells to recognize and eliminate cancer cells.1,3-5 There are various immuno-oncology agents available and in development that can activate an immune response at various points along the immune cycle.3-5 However, treatment challenges persist and most cancer patients cannot benefit from current immuno-oncology therapies.

There are two components of the immune response that make up the immunity cycle4,5:

  • Innate immune response
    • The innate immune response is an antigen-independent response that is immediate and has no immunologic memory.4,5 Natural killer (NK) cells, dendritic cells (DCs), innate lymphoid cells (ILCs), and macrophages are the primary innate immune cell types.6,7
  • Adaptive immune response
    • The adaptive immune response is an antigen-dependent and antigen-specific response with the capacity for immunologic memory.4,5 T cells and B cells are the primary adaptive immune cell types.

The innate immune response is a critical first defense against microbes. It consists of a range of cell types and mechanisms that quickly respond to block microbial invasion. This system can detect the presence of a threat by recognizing microbial structures that are common among many types of invaders but not present in the host. The innate response is also important for activating and directing the adaptive response.

In a normal immune response:

  • Damage-associated molecular pattern (DAMP) molecules released from microbes or infected cells activate innate immune cells that are capable of rapidly responding to the threat.8,9
    • Stimulators of the innate immune response include proinflammatory cytokines (TNF-α, IL-1, IFN-α), bacterial and viral sensing pathways, and immune cell factors (CD40, antibodies bound to an invader). Inhibitors include IL-10, IL-4, and IL-13.4,10
  • These same danger signals activate and mature DCs, the first step in the adaptive immune response.8,9

Steps in an adaptive immune response include:

  • Antigen presentation to T cells by activated and mature antigen-presenting cells (APCs)
    • Mature DCs capture and process proteins from the threat (antigens for the adaptive immune system to recognize) and migrate to draining lymph nodes.10
    • Major histocompatibility complex (MHC) proteins on the surface of mature DCs present the captured antigens to the T-cell receptor on T cells4,5 along with the costimulatory proteins the T cells need to respond.
      • MHC class I complexes are recognized by cytotoxic CD8+ T cells.11
      • MHC class II complexes are recognized by CD4+ T cells.11
  • T-cell expansion and migration
  • T-cell killing
  • Resolution of the response when the threat is no longer present

When activated, several innate immune cell populations can directly kill tumor cells. NK cells can recognize tumor antigens, leading to innate cell activation and tumor cell destruction, and macrophages can kill tumor cells through secretion of nitric oxide species.4,10

Tumor-specific antigens released by dying tumor cells are recognized by DCs, which then process and transport the tumor-specific antigens to draining lymph nodes.4,10

Priming and Activation of T Cells

  • If an immunogenic stimulus is present, effector T-cell responses against the tumor-specific antigens are activated.4,10
  • In the absence of a stimulus, immature DCs will present the antigens to T cells and induce T-cell tolerance.4,10
  • The balance between CD8+/CD4+ T cells and Tregs within a tumor is important in determining the response to anti-PD1/PD-L1 agents.4
  • Stimulators of T-cell priming and activation include cytokines and surface receptors such as OX40, CD28, GITR, and CD27.4,12 Inhibitors include CTLA4, PD-1, TIM3, LAG3, TIGIT.7,13,14

Trafficking of T Cells to Tumors

  • The trafficking of activated T cells and other immune cells to the tumor is a highly regulated and dynamic process.15
  • Overcoming the barriers that restrict targeting of T cells to the tumor site is critical.
  • Stimulators include CX3CL1, CXCL9, CXCL10, and CCL5.12

Recognition of Cancer Cells by T cells

  • The T-cell receptor (TCR) specifically recognizes and binds to the corresponding tumor antigen.4
  • Response may be reduced if the cancer cell10:
    • Has lost expression of the tumor antigen
    • Has downregulated their expression of MHC class I molecules
    • Expresses surface molecules (ie, PD-L1) that engage receptors on activated T cells (ie, PD-1), leading to T-cell exhaustion

Killing of Cancer Cells

  • Killing of the cancer cell releases additional tumor-associated antigens.4
  • Stimulators include IFN-γ.4,10 Inhibitors include PD-1, LAG3, TIM3, TIGIT, B7-H4, and TGFβ.4,10,16

The T-cell checkpoints are off-switches and part of the normal resolution and inhibition of an immune response. These include CTLA4, PD-1, LAG3, TIM3, TIGIT, and others still being discovered.


For tumors to grow, mechanisms must be in place to evade the immune response that might recognize and eliminate the mutated cells. This can occur through mechanisms that suppress the response and through selection of mutated cells that cannot be recognized by the immune system.

Many tumor-cell–intrinsic and –extrinsic factors contribute to immune evasion and immuno-oncology therapy resistance.17

Intrinsic Mechanisms of Resistance

  • Intrinsic mechanisms are those that involve the tumor cell itself.
  • Mechanisms of primary resistance include alteration of signaling pathways (ie, JAK, MAPK, PIK3, WNT), lack or loss of tumor-specific antigens, alteration in antigen-presenting machinery, constitutive PD-L1 expression, and loss of human leukocyte antigen (HLA) expression.17
  • Mechanisms of acquired resistance include loss of target antigen or HLA expression at recurrence, altered IFN signaling, loss of T-cell functionality, and loss of sensitivity to complement-induced, T cell-induced, or natural killer (NK) cell-induced lysis.17

Extrinsic Mechanisms of Resistance

  • Extrinsic mechanisms involve components of the tumor microenvironment other than the tumor cell.
  • Extrinsic mechanisms of primary and acquired resistance include expression of PD-1 and other immune checkpoints, T-cell exhaustion, the accumulation of myeloid-derived suppressor cells (MDSCs), and cytokine and metabolite release in the tumor microenvironment.17,18

Therapeutic Potential

The introduction of immune checkpoint inhibitors in oncology has increased the potential for durable responses and shifted therapeutic attention to extending the tail of the survival curve. However, not all patients respond to currently available immunotherapy agents (ie, PD-1/PD-L1 and CTLA antibodies).

The potential to address a range of additional immune mechanisms of resistance, and to activate an immune response at additional points along the immune cycle makes continued research in immuno-oncology vital to the evolution of cancer therapy. Novel immuno-oncology targets and pathways include OX40 and CD40.10,12 Due to the multiple mechanisms of immune-suppression, combination immuno-oncology regimens may also help address patient needs.

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  2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.
  3. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27(8):1492-1504.
  4. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1-10.
  5. Warrington R, Watson W, Kim HL, Antonetti FR. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011;7 Suppl 1:S1.
  6. Liu Y, Zeng G. Cancer and innate immune system interactions: translational potentials for cancer immunotherapy. J Immunother. 2012;35(4):299-308.
  7. Marcus A, Gowen BG, Thompson TW, et al. Recognition of tumors by the innate immune system and natural killer cells. Adv Immunol. 2014;122:91-128.
  8. Hernandez C, Huebener P, Schwabe RF. Damage-associated molecular patterns in cancer: a double-edged sword. Oncogene. 2016;35(46):5931-5941.
  9. Ferguson TA, Choi J, Green DR. Armed response: how dying cells influence T-cell functions. Immunol Rev. 2011;241(1):77-88.
  10. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489.
  11. Wieczorek M, Abualrous ET, Sticht J, et al. Major histocompatibility complex (MHC) class I and MHC class II proteins: conformational plasticity in antigen presentation. Front Immunol. 2017;8:292.
  12. Franciszkiewicz K, Le Floc'h A, Boutet M, Vergnon I, Schmitt A, Mami-Chouaib F. CD103 or LFA-1 engagement at the immune synapse between cytotoxic T cells and tumor cells promotes maturation and regulates T-cell effector functions. Cancer Res. 2013;73(2):617-628.
  13. Riella LV, Paterson AM, Sharpe AH, Chandraker A. Role of the PD-1 pathway in the immune response. Am J Transplant. 2012;12(10):2575-2587.
  14. So T, Lee SW, Croft M. Tumor necrosis factor/tumor necrosis factor receptor family members that positively regulate immunity. Int J Hematol. 2006;83(1):1-11.
  15. Slaney CY, Kershaw MH, Darcy PK. Trafficking of T cells into tumors. Cancer Res. 2014;74(24):7168-7174.
  16. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy–inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18(24)6580-6587.
  17. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168(4):707-723.
  18. Gabrilovich DI. Myeloid-derived suppressor cells. Cancer Immunol Res. 2017;5(1):3-8.

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