Cancer Immunoediting

Cancer Immunoediting

• The immune system can both destroy tumors and promote cancer development.
• Immunoediting describes the dynamic role of the immune system in cancer, including destroying cancer cells and influencing aggressive malignant cell development.
• Immune surveillance involves the immune system continually surveying dividing cells to ensure normal function, destroying abnormal cells.
• Compromised immune systems, like in AIDS patients, lead to higher cancer rates due to impaired immune surveillance.
• The spontaneous regression of malignancies demonstrates the immune system's role in tumor destruction.
• Chronic inflammation can promote malignancy, indicating the immune system's involvement in tumor promotion.

Immunoediting Hypothesis

• Immunoediting combines immune surveillance and tumor progression, illustrating the immune system's dual role.
• Cancer transmission through organ transplants supports immunoediting theory.
• Both innate and adaptive immune systems are involved in cancer immunoediting.
• The immunoediting hypothesis highlights the immune system's protective and tumor-sculpting roles, explaining how less immunogenic tumor cells evade destruction.

Phases of Immunoediting

• The three phases include elimination, equilibrium, and escape.

Phase 1: Elimination

• Innate and adaptive immune systems work together to eliminate tumor cells early on.
• Innate immune cells recognize damage-associated molecular patterns (DAMPs) from dead cancer cells, producing interferons (IFN-γ).
• IFN-γ activates dendritic cells and promotes adaptive immune responses.
• Mice lacking certain immune components show earlier and deeper neoplasias.
• Spontaneous tumor regression provides evidence for elimination.
• Perforins and granzymes released from cytotoxic lymphocytes trigger a conserved immune pathway, resulting in tumor cell death.
• Tumour cell death process:
  • Cytotoxic lymphocytes recognize and bind to target tumor cells, forming an immunological synapse.
  • The microtubule-organizing center (MTOC) reorients, and secretory granules move toward the presynaptic membrane.
  • Secretory granules fuse with the lymphocyte's presynaptic membrane.
  • Perforin and granzymes are released into the synaptic cleft, with perforin creating pores in the tumor cell membrane.
  • Granzymes enter the tumor cell's cytosol, inducing apoptosis.

Phase 2: Equilibrium

• Tumor cells enter dormancy, and a dynamic equilibrium is maintained via immune suppression of tumor outgrowth.
• The phase often lasts for a long time.
• Experiments with immunocompetent mice treated with low-dose carcinogens show occult cancer cells were present despite no visible tumors.
• Depletion of T cells and IFN-γ leads to rapid tumor growth at the carcinogen injection site.
• Adaptive immune system cytokines, such as IL-12, control the mechanism behind tumor dormancy.

Phase 3: Escape

• Tumor cells emerge with mutations or epigenetic alterations enabling them to evade immune recognition or destruction.
• It leads to the formation of progressively growing, visible tumors.
• Immune escape is characterized by:
  • Decreased expression of tumor antigens or antigen immunogenicity
  • Increased resistance to cytotoxic effects of immune effectors
  • Inhibition of the immune system by immunosuppressive molecules

Tumor Microenvironment (TME)

• M2-skewed macrophages are associated with poor patient outcomes.
• Th1 T-cells, CD8+ T cells, M1-skewed macrophages, and B cells are associated with improved outcomes.
• Immunoscore is a metric describing CD8+ T cell density within the tumor and at the invasive margin.
• High immunoscore in colorectal cancer correlates with better prognosis; low immunoscore correlates with poor prognosis.
• Immunoscore is better than standard TMN staging for predicting clinical outcomes in colorectal cancer.

Immune Escape Mechanisms

• Immune escape is evaded by loss of antigen expression, resistance to death signals, release of immunosuppressive molecules, and activation of immune checkpoints.

Loss of Tumor Antigen Expression

• It can be mediated by:
  • lack of strong rejection antigens.
  • loss of antigen-processing function.
  • loss of antigen-presenting function (MHC-dependent or independent).
• MHC-dependent loss involves direct loss of MHC protein expression, related to invasive and metastatic lesions.
• It occurs due to mutations in the proteasome or transporter proteins.
• MHC-independent loss is linked to disease progression and can occur independent of reduced MHC class 1 expression.
• The immunodominance theory explains propagation of antigen-deficient variants
  • Immunodetection: detection of one or a few epitopes on a given target.
  • Diversion: parental tumor cells divert attention from tumor cells that have suppressed antigen expression.
  • Elimination: parental cells are eliminated, establishing a new hierarchy.
• Loss of tumor antigen expression decreases recognition and destruction from both innate and adaptive immune systems.
• Hypoxia increases the shedding of MICA receptors, increasing the ability to evade NK cell-mediated lysis.

Resistance to Death Signals

• Tumor cells develop resistance to cytotoxic effects via:
  • induction of anti-apoptotic mechanisms
  • expression of anti-apoptotic effector molecules such as BCL-2.
  • down regulation of apoptosis-inducing receptors like FAS and TRAIL.
• Defective death receptor signaling is caused by:
  • mutations in FAS and TRAIL receptors
  • mutations in FAS Associated Death Domain caspases
  • upregulation of c-FLIP (caspase 8 inhibitor).

Release of Immunosuppressive Molecules

• Tumour cells release immunosuppressive molecules, including cytokines, enzymes, and prostaglandins.
• VEGF inhibits dendritic cell differentiation and maturation, impairing T cell responses.
• IL-10 inhibits dendritic cell function and IL-12 production, dampening antigen presentation and Th1 responses.
• TGF-beta is linked to disease progression and inhibits lymphocyte activation, proliferation, and function.
• Enzymes like IDO and Arginase cause local depletion of amino acids, suppressing immune responses.
• Prostaglandin E2 promotes immune suppression in chronic inflammation and cancer.

Activation of Immune Checkpoints

• Tumors co-opt these to evade:
  • CTLA-4
  • PD-1/PD-L1/L2 pathways.

CTLA-4 Checkpoint

• CTLA-4 on T cells competes with CD28 to bind CD80/CD86 on APCs, inhibiting T cell activation and maintaining immune balance.
• Tumor cells exploit CTLA-4, preventing CD28 from activating T cells and suppressing cytotoxic T lymphocyte (CTL) activity.
• Suppression mainly happens in secondary lymphoid organs.

PD-1/PD-L1 Immune Checkpoint

• PD-1 limits T cell activity during infection and prevents autoimmunity.
• It is found on T cells, Tregs, B cells, NK cells, monocytes, and dendritic cells.
• PD-1 binds to PD-L1 or PD-L2, which is triggered by inflammatory cytokines like IFN-γ.
• Binding causes T cell dysfunction and reduces anti-tumor immunity.
• Tumor cells increase PD-L1 expression via IFN-γ, mutations, or hypoxia, inhibiting T cell activity in the TME.
• Unlike CTLA-4, PD-1 acts mainly within the tumor microenvironment.

Immunotherapies

• Checkpoint blockade (ICB) is used with antibodies against PD1/PD-L1/L2 pathways.

Inflammation and Cancer

• Inflammation can be occurs over a short (acute) and long (chronic) period
• Acute inflammation is associated with a protective adaptive immune response to pathogens and cancer
• Chronic inflammation is associated with tumorigenesis, causing genotoxic stress and inducing cellular proliferation in early stages.
• IL-1 beta can promote immune response against tumors by facilitating tumor recognition if present at later stages of tumorigenesis.
• Inflammatory cells can assist in tumor escape by being activated by cancer-derived products like VEGF, suppressing anti-tumor immunity.
• Cancer is described as a wound that won't heal, as components facilitating wound healing are present within the TME.
• Examples of components of the TME are:
  • Chemokines
  • Angiogenesis
  • Tumour growth
  • Invasion and migration
  • Metastasis
  • Immune cell recruitment

Aspirin

• Regular aspirin use may decrease cancer risk, especially colorectal cancer, due to its anti-inflammatory and immunosuppressive effects.

Immunotherapy

• Immunotherapy harnesses the immune system to fight disease, recognizing, targeting and destroying cancer cells.
• It involves drugs, such as monoclonal antibodies, or cell-based therapies, where patient’s cells are modified.
• Five main classes of immunotherapy are oncolytic viruses, vaccines, cell-based immunotherapies, antibody-targeted therapies, and immunomodulators.

Oncolytic Viruses

• Oncolytic viruses infect cancer cells and trigger cell death via virus-induced lysis
• They can act as vaccines and be loaded with immunomodulatory genes or combined with other immune therapies.
• Tumour cells are inclined toward oncolytic viral infection because they have altered interferon signalling, allowing for immune escape
• Oncolytic virus therapy can cause the release of tumour antigens from lysed cells, triggering anti-tumour immune responses.

Vaccines

• Vaccines can be preventative or therapeutic.
• Bacillus Calmette-Guerin (BCG) prevents TB and recurrence of bladder cancer after surgical removal of the primary tumour.

Cell-Based Immunotherapies

• Aka adoptive cell therapies, they manipulate a patient's own immune cells ex vivo.
• Cell Based Immunotherapy Classes include:
  • Dendritic cell-based therapies: monocytes differentiate into dendritic cells ex vivo and re-infused into patient.
  • Cytotoxic T cell therapies: T cells are modified and activated ex vivo and re-administered with immunostimulatory therapy
• Sipuleucel-T therapy is an autologous cellular immunotherapy for metastatic castrate resistant prostate cancer but only improved survival, not time-to-progression.
• Sipuleucel-T cultures peripheral blood mononuclear cells with PAP-GM-CSF - a chemokine that activates and expands APCs.
• It uses a tumour antigen (PAP) to elicit an immune response, so it is also a vaccine therapy.
• Cell based immunotherapies increase antigen presentation of tumour specific epitopes, in vitro activation of cells allows cells to be released from the inhibitory factors present in vivo, can generate large numbers of anti-tumour T cells, can proliferate in vivo and maintain their anti-tumour functions.
• Engineered receptors are added to T cells
• T cells can recognize tumour-specific antigens
• Modified T cells are grown in vitro and re-infused
• They target and kill cancer cells.
• CAR-T therapy is approved for CD19+ leukemias and lymphomas,.

Limitations of CAR-T Therapy

• Antigens need to be on most or all tumour cells for treatment to work.
• Antigen should not be on healthy cells to prevent off-target damage.
• Cells must be engineered for antigen specificity, able to proliferate, survive, and reach tumours effectively.

Antibody-Targeted Therapies

• They recognize tumour-associated antigens present on the surface of malignant T-cells.
• Antibody-targeted therapies classes Include:
  • Naked Monoclonal antibodies
  • Antibody Drug Conjugates
  • Bispecific antibodies

Naked Monoclonal Antibodies

• They inhibit signalling pathways require for survival
• They initiate antibody dependent cell-mediated cytotoxicity (ADCC).
• Rituximab is licensed for non-hodgkin's lymphoma, and is specific for CD20.

Antibody Drug Conjugates

• Antibodies are conjugated to anti-cancer drugs so there is local delivery of the anti-cancer drug when the antibody binds to the tumour cell.

Bi-Specific Antibodies

• Antibodies are engineered to recognize two different targets (usually a tumour and immune cell) with the goal of enhancing anti-tumour recognition.

Immunomodulators

• They modulate pathways that regulate the activation of the immune system
• They either inhibit pathways that function to dampen the immune response or stimulate pathways known to activate the immune system.
• They are most effective in solid tumours.
• Examples of immunomodulators are:
  • ICB therapies
  • Cytokines
  • Adjuvants
• Targeted therapies work best in homogenous tumours, and ICB therapy works best in heterogenous tumours.

ICB Therapy

• ICB therapy can be applied by CTLA-4 Blockade or PD-1/PD-L1 Blockade
• Blocking CTLA-4 boosts anti-tumour immune response and causes tumour regression with a known survival benefit in clinical trials (ipilimumab is drug name).

CTLA-4 Blockade Mechanism

• Some cancer cells overexpress CTLA-4, which binds CD80/CD86
• CTLA-4 blocks CD28
• Blocking CTLA-4 restores CD28:CD80/86 interaction therefore activates T cells.

PD-1/PD-L1 Blockade Therapy

• PD-1 pathway reduces T cell activity and limits autoimmunity.
• Tumours hijack this to evade immune system.
• The PD-1 receptor can be found on T cells, B cells, NK cells, DCs.
• Ligands (PD-L1/PD-L2) can be found on myeloid + tumour cells
• PD-1/PD-L1 Blockade Provides the Therapeutic Effects:
  • Prevents T cell exhaustion
  • Suppresses intra-tumour Tregs
  • Enhances NK cell tumour activity
  • Blocks Treg activation
• Multiple PD-1/PD-L1 drugs are now approved for various solid tumours.
• The First Approval was Pembrolizumab (anti-PD-1) in 2014 for metastatic melanoma.
• Combination therapy is now explored with other anti-cancer therapies to boost effectiveness and duration of response.

Limitations of ICB Therapy

• There are adverse events like immune-related side effects
• There is limited patient response.
• It can lead to predictive biomarkers and new checkpoint molecules.