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Revealing the Potential of the Immune System in Cancer

Strategies that leverage the immune response may play a key role in the investigation of novel therapies

  • Innate and adaptive immunity act as complementary networks of self-defense against foreign threats such as pathogens and cancer1
  • The immune system is able to recognize foreign threats (nonself) as distinct from normal cells (self)2-4
    • In cancer, normal cells have mutated into tumor cells and are recognized as nonself by both the innate and adaptive immune systems5,6

Tumor Microenvironment

Diagram of a tumor microenvironment

Innate immunity: Natural killer (NK) cells mediate a rapid, antigen-independent response against cancer

  • The innate immune response is the body’s first line of defense against pathogens and cancer; it responds immediately and independently of antigens1,5,7
  • It is constantly on alert and can rapidly identify and attack tumor cells:
    • While antigen specificity does not limit the speed and scope of the innate immune response, it is still regulated to protect normal cells. It recognizes activating and inhibitory signals from target cells to distinguish self from nonself, allowing for the elimination of tumor cells while sparing normal cells8-10
  • NK cells are the main effector cells of the innate immune system11,12
  • By engaging activating receptors, NK cells recognize tumor cells as nonself and target them for destruction9

Adaptive immunity: capacity cytotoxic T cells to mediate specific and sustained responses to tumor antigens

  • The adaptive immune response is antigen-specific and produces durable responses1,7
  • Although not immediate, once activated the adaptive immune response can be sustained through immune memory13
  • Cytotoxic T cells are effector
    of the adaptive immune system1

Innate and Adaptive Immune Response

Diagram of the innate and adaptive immune response
  • In both the innate and the adaptive immune responses, immune cells have the potential to recognize and eliminate abnormal cells such as tumor cells
  • There are three principal stages of immune response:

Diagram of the first principal stage of immune response - presentation, infiltration, and elimination

  • Presentation: the innate immune system rapidly identifies and attacks tumor cells and causes tumor cell death. This process releases tumor antigens that can activate the cytotoxic T cells of the adaptive immune system15,30
  • Infiltration: immune cells are attracted by tumor antigens and other factors to the tumor site, where they invade and attack30
  • Elimination: activated cytotoxic T cells recognize tumor cells as the source of the antigen and target them for elimination30

The balance of activating and inhibitory pathways regulates antitumor immunity

  • The antitumor activity of NK and cytotoxic T cells is regulated through a network of activating and inhibitory signaling pathways4,31,32
  • Activating pathways trigger an immune response, whereas inhibitory pathways, such as immune checkpoint pathways, counterbalance immune activation, enabling the immune system to attack tumor cells while sparing healthy cells32

Tumor cells leverage activating and inhibitory networks to evade the antitumor response

  • The complex network of activating and inhibitory pathways enables the antitumor immune response to detect and eliminate tumor cells at any point in tumor development16
  • However, tumors seek to evade or suppress the body’s natural ability to fight cancer, and they can evolve at any phase of growth to “outsmart” the antitumor immune response16,33

Tumor cells recruit inhibitory immune and stromal cells that suppress the immune response and contribute to tumor immune evasion

  • The tumor microenvironment consists of different cell types that help tumor cells evade antitumor immune activity. These include immune cells, such as effector and non-effector cells, as well as structural cells, known as stromal cells, that surround the tumor34,35
    • Non-effector cells suppress the antitumor immune response by inhibiting effector cell function34
    • Stromal cells can temper effector-cell antitumor activity by acting as a barrier to immune cell infiltration of the tumor34,36
    • As tumors evolve, they can influence the activation and composition of cells within the tumor microenvironment33

Diagram of noninflamed tumor converting to an inflamed tumor through tumor antigen presentation

The tumor microenvironment can be converted from noninflamed to inflamed

  • Reestablishing fundamental stages of immune response that are impaired within noninflamed tumors—presentation, infiltration, and elimination—is a key strategy to improve the broad potential of Immuno-Oncology
  • Ongoing research aims to promote inflammation within tumors to increase susceptibility to antitumor immunity

Converting noninflamed to inflamed: enhancing tumor antigen presentation

  • Tumor antigens, which may be sparse in noninflamed tumors, are required for initiating an adaptive antitumor immune response1,37
  • In addition to mutated tumor-specific proteins, proteins that are highly expressed on tumor cells may also serve as tumor antigens that can potentially activate cytotoxic T cells53-55
  • Preclinical data suggest that promoting tumor cell death by cytotoxic agents such as chemotherapeutics, irradiation, or infection with oncolytic viruses can stimulate tumor antigen release and can initiate an immune response56-62
  • Other preclinical data suggest that vaccines may introduce tumor antigens to APCs and stimulate cytotoxic T-cell function63,64
  • Finally, optimizing both tumor antigen presentation and adaptive immune response may further promote an inflamed tumor environment35

Converting noninflamed to inflamed: enhancing innate immune components

  • Innate immune system components provide activating signals that can increase APC priming of T cells and immune cell infiltration of the tumor microenvironment18,35,65
  • Preclinical studies suggest that stimulating these components of innate immunity can increase cytotoxic T-cell infiltration into noninflamed tumors66,67

Diagram of a noninflamed tumor converting to an inflamed tumor through chemokine production

Converting noninflamed to inflamed: enhancing chemokine production

  • Noninflamed tumors also have little to no expression of chemokines, resulting in impaired T-cell recruitment40
  • Preclinical data suggest that stimulating chemokine production, such as by irradiation exposure, can help restore cytotoxic T-cell recruitment and promote tumor infiltration58,68
    • Furthermore, data suggests stimulating or inhibiting multiple pathways (eg, chemokine production and checkpoint inhibitors) may further promote an inflamed tumor microenvironment35

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REFERENCES–Revealing the potential of the immune system in cancer

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