Tumor Immunology - Definition, features

Tumor immunology is the study of interaction between immune system and tumor cells. It deals with how body recognize abnormal neoplastic cells and how these cells escape from immune response.

Tumor cells are formed due to abnormal and uncontrolled growth of cells. These cells may express new antigens on their surface. These antigens are recognized by immune cells and immune response is produced against tumor. This immune response may destroy tumor cells or may only control their growth for some time.

Cancer immunoediting is an important concept of tumor immunology. It explains the dual role of immune system in cancer. The immune system acts as a tumor suppressor by killing malignant cells. At the same time it also helps in selection of tumor cells which are more resistant to immune attack. This is referred to as immunoediting.

The process of cancer immunoediting occurs in three phases. These are elimination, equilibrium, and escape.

Elimination phase is also called immune surveillance. In this phase, both innate immunity and adaptive immunity recognize and destroy transformed cells. Natural killer cells, macrophages, cytotoxic T cells and other immune cells take part in this process. Tumor cells are removed before they form visible tumor.

Equilibrium phase occurs when some tumor cells are not completely destroyed. In this phase, immune system controls the growth of tumor cells. The tumor remains in dormant condition. During this period tumor cells may undergo mutation and lose their strong antigenic characters. So they become less recognizable to immune system.

Escape phase occurs when tumor cells avoid immune control. These cells grow continuously and form clinically detectable cancer. In this phase tumor cells may reduce antigen expression, produce immunosuppressive factors and inhibit the function of T cells.

Tumor microenvironment (TME) is the surrounding area of tumor which contains tumor cells, immune cells, blood vessels, fibroblasts, extracellular matrix and soluble factors. It has a major role in tumor growth and immune escape.

Tumor cells modify their microenvironment for survival. They rapidly use nutrients and starve the immune cells. They produce lactate and increase acidity around the tumor. They also make the extracellular matrix stiff, which block the entry of immune cells into tumor tissue.

The tumor also produces different suppressive signals. These signals reduce the activity of T lymphocytes and other immune cells. Due to this, immune cells become weak or exhausted and cannot destroy tumor cells properly.

The study of tumor immunology is important for development of cancer immunotherapy. Immunotherapy is used to activate patient’s own immune system against cancer. It helps to remove immune suppression, restore T cell activity and destroy tumor cells.

Relationship Between the Immune System and Tumors

The immune system and tumors have a close relation. Immune system can recognize abnormal tumor cells and destroy them. But tumor cells can also change themselves and escape from immune attack.

This relation is not simple. The immune system acts as a protective system against cancer. At the same time it also gives pressure on tumor cells. Due to this pressure, only those tumor cells survive which are more resistant to immune response. This process is called cancer immunoediting.

Cancer immunoediting occurs in three phases. These are elimination, equilibrium, and escape.

Elimination phase is the first phase. In this phase, innate immune cells and adaptive immune cells recognize the developing tumor cells. Natural killer cells, T cells, macrophages and other immune cells destroy these transformed cells before they form visible tumor mass.

Equilibrium phase starts when some tumor cells are not destroyed completely. In this phase, immune system keeps the tumor cells under control. Tumor growth remains suppressed for long time. But during this time tumor cells undergo mutation and gradually change their antigenic characters.

Escape phase occurs when mutated tumor cells overcome immune control. These cells grow and divide continuously. Then the tumor becomes clinically detectable cancer. In this stage immune system cannot control the tumor properly.

Tumor cells escape by hiding their antigens. They may stop expressing identifying markers on their surface. They can also reduce MHC molecules. Due to this, cytotoxic T cells cannot recognize tumor cells properly.

Tumor cells also create metabolic starvation. They consume large amount of glucose from the surrounding area. So tumor infiltrating immune cells do not get enough nutrients. These immune cells become weak, exhausted and unable to function normally.

Tumors produce large amount of lactic acid. This makes the tumor area acidic. The acidic condition inhibits attacking T cells and dendritic cells. It also supports regulatory T cells (Tregs) which suppress anti-tumor immunity.

Tumors can form physical barriers around them. They increase production and cross-linking of collagen. This makes a dense and stiff matrix. Due to this, immune cells cannot easily enter into the tumor core.

Tumors also recruit suppressor cells. Some of the important suppressor cells are regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and M2 macrophages. These cells suppress the natural anti-tumor immune response.

Tumor Antigens

Tumor antigens are the structurally different proteins present on tumor cells. These antigens help the immune system to identify the malignant cells from normal healthy cells.

Tumor antigens are mainly of three types. These are Tumor-associated antigens (TAAs), Tumor-specific antigens (TSAs) or Neoantigens, and Cancer/testis antigens (CTAs).

1. Tumor-associated antigens (TAAs)

Tumor-associated antigens are normal self proteins which are over expressed or abnormally expressed in cancer cells. These antigens are also present in normal body cells but in lower amount.

Because these antigens are self antigens, the immune system may show tolerance against them. So T cells usually recognize them with low affinity. The immune response against these antigens is not always very strong.

Some of the important examples of TAAs are WT1, Her2/neu, and carcinoembryonic antigen (CEA).

2. Tumor-specific antigens (TSAs) or Neoantigens

Tumor-specific antigens are antigens which are present only on tumor cells. These are absent from normal healthy cells of the body.

These antigens mainly arise due to somatic mutation in tumor cells. They may also be produced from oncogenic viral proteins. As these antigens are new and foreign for the body, they are called neoantigens.

These antigens are not affected by normal immune tolerance. So they can produce strong and specific cytotoxic T cell response against tumor cells.

3. Cancer/testis antigens (CTAs)

Cancer/testis antigens are special type of tumor antigens. Normally these antigens are expressed only in male germline cells of testis and sometimes in placental tissue.

In many cancers, these antigens are abnormally re-expressed. The normal testis tissue does not properly present antigens to immune system because of blood-testis barrier and lack of MHC class I expression.

So when CTAs are present on cancer cells, the immune system recognizes them as foreign. Due to this, they are important target for cancer immunotherapy.

Some of the important examples of CTAs are MAGE family, MAGE-1, and NY-ESO-1.

Recognition Process of Tumor Cells by the Immune System

Expression of tumor antigens
Tumor cells express different tumor antigens on their surface. These antigens help the immune system to identify malignant cells from normal healthy cells.
Release of antigens and danger signals
During immunogenic cell death, tumor cells release antigens and danger signals. These signals are called DAMPs. Examples are ATP, HMGB1, and calreticulin.

Capture by antigen presenting cells
Dendritic cells and macrophages reach the tumor area. They engulf the dying tumor cells or released antigens. This process is called phagocytosis.
Antigen processing and presentation
The captured antigens are broken into small peptide fragments. These peptides are presented by MHC class I and MHC class II molecules.
T cell activation
The mature APCs move to lymph node. Here TCR of CD8+ T cells and CD4+ T cells recognize antigen-MHC complex. Then T cells become activated and divide rapidly.

Tumor cell killing
Activated cytotoxic T cells and NK cells return to tumor site. They recognize tumor cells and destroy them by perforin, granzymes, and Fas-FasL pathway.

Cells Involved in Anti-Tumor Immunity

Cytotoxic T cells– These are also called CD8+ T cells. These are main killing cells of adaptive immunity. They recognize specific tumor antigens present on cancer cells. Then they kill cancer cell by releasing perforin and granzymes. They also secrete IFN-γ and TNF-α.
Helper T cells– These are also called CD4+ T cells. These cells help in making anti tumor immune reaction strong. Mainly Th1 cells are important in this process. They produce IFN-γ and TNF-α. These cytokines promote anti tumor activity and may stop cell cycle of tumor cells.

Natural killer cells– Natural killer cells (NK cells) are innate immune cells. They can detect abnormal malignant cells without specific antigen presentation. They do not need MHC restriction for killing. They release lytic particles in directed way and destroy tumor cell.
Dendritic cells– Dendritic cells (DCs) are strong professional antigen presenting cells. They capture tumor antigens from tumor area. Then they migrate to lymph nodes. In lymph node they present antigen to resting T cells and activate them.
Macrophages– Macrophages are innate immune cells. They may become anti tumor type called M1 macrophages. These cells use aerobic glycolysis and attack tumor cells. They also release pro-inflammatory cytokines. But tumor may reprogram them into M2 macrophages, which suppress immunity and help tumor growth.

Neutrophils– Neutrophils are most abundant innate immune cells. They act as first line defense cells. They may become anti tumor N1 neutrophils and produce reactive oxygen species (ROS). But in tumor condition they can also change into N2 neutrophils. This type support tumor growth.
B cells– B cells help in anti tumor immunity. They produce tumor specific antibodies. They also present antigens to T cells and release immunomodulatory molecules. They are commonly present in tumor-associated tertiary lymphoid structures.
Regulatory T cells– Regulatory T cells (Tregs) normally suppress unwanted immune reaction and maintain immune balance. But tumor recruits these cells in tumor area. These cells suppress anti tumor function of T cells and NK cells.

MDSCs– Myeloid-derived suppressor cells (MDSCs) are suppressor immune cells. These cells are expanded by tumor. They inhibit cytotoxic T cells and NK cells. So anti tumor immune response become weak.

Mechanisms of Immune Response Against Tumors

Immune surveillance– It is the first defense mechanism against tumor cells. Innate immunity and adaptive immunity work together in this process. They continuously detect abnormal transformed cells and destroy them before they form visible tumor.
Antigen release– When tumor cells become stressed or die, they release tumor antigens. This mainly occurs during immunogenic cell death (ICD). Along with antigens, some danger signals are also released.

Danger signals– The danger signals are called DAMPs. These signals attract and activate immune cells. Important DAMPs are ATP, calreticulin, and HMGB1. ATP acts as find me signal. Calreticulin acts as eat me signal.
Antigen capture– Dendritic cells and macrophages reach the tumor site. They recognize the danger signals. Then they engulf dying tumor cells and released antigens. This process is called phagocytosis.
DC maturation– After taking tumor antigen, dendritic cells become mature. This maturation is stimulated by inflammatory signals like HMGB1 and Type I interferons. Mature dendritic cells become more active for antigen presentation.

Lymph node migration– The antigen loaded dendritic cells move from tumor site to local draining lymph node. In lymph node they meet naive T cells. This step is important for starting adaptive anti tumor immunity.
T cell priming– In lymph node, dendritic cells process the tumor antigen into small peptide. Then they present it through MHC molecules. MHC class I activates CD8+ T cells and MHC class II activates CD4+ T cells. This activation is called cross-priming.
Clonal expansion– After activation, tumor specific T cells divide rapidly. Many effector T cells are formed from one activated T cell. This is called clonal expansion.

Tumor infiltration– Activated T cells leave the lymph node and enter blood circulation. They move towards tumor by chemical attractants called chemokines. Important chemokines are CXCL9 and CXCL10. Then they enter into tumor microenvironment.
Tumor killing– Cytotoxic CD8+ T cells and Natural killer cells (NK cells) recognize malignant cells in tumor area. They kill tumor cells by releasing perforin and granzymes. Perforin forms pores and granzymes enter the cell and cause cell death.
Death pathways– Tumor cells are also killed by death receptor pathways. The important pathways are Fas-FasL pathway and TRAIL pathway. These pathways induce apoptosis in tumor cells.

Cytokine action– Type I interferons (IFN-α/β) and IFN-γ increase anti tumor immune response. They increase antigen presentation and make immune cells more active. IFN-γ also helps in arrest of tumor cell growth.
Response amplification– During this process many cytokines are released. These cytokines increase the activity of T cells, NK cells, and antigen presenting cells. So the anti tumor response become stronger.

Tumor Immune Evasion Mechanisms

Tumor cells may reduce or lose tumor antigens from their surface. They can also decrease MHC class I molecules. So cytotoxic T cells cannot recognize tumor cells properly. This makes tumor cells hidden from adaptive immune response.

Tumor cells express CD47 and CD24 on their surface. These molecules act as don’t eat me signals. They bind with receptors present on macrophages and stop phagocytosis. So macrophages cannot engulf tumor cells.
Tumor cells consume very high amount of glucose. This occurs through aerobic glycolysis or Warburg effect. Due to this, nutrients become less in tumor area. Tumor infiltrating T cells become starved and exhausted.
Tumor cells produce high amount of lactic acid and branched-chain keto acids. These substances make the tumor area acidic and toxic. This acidic condition disturb T cell function and suppress normal immune activity.

Acidic tumor condition suppress the maturation of dendritic cells. So proper antigen presentation does not occur. Due to weak antigen presentation, activation of T cells become reduced.
Tumor microenvironment can change macrophages into M2 macrophages. These macrophages are immunosuppressive in nature. They do not destroy tumor cells strongly. They help in tumor growth and immune escape.
Tumor metabolites also support regulatory T cells (Tregs). These cells suppress anti tumor immune response. They inhibit T cells and other effector immune cells.

Tumors produce large amount of extracellular matrix proteins. Mainly collagen is overproduced and cross-linked. This forms dense and stiff matrix around tumor. So immune cells cannot easily enter into tumor core.
The stiffness of tumor matrix also affect immune cells. Immune cells sense this mechanical force. High stiffness can stop dendritic cell maturation and disturb T cell activation.
Physical force from stiff tumor matrix may reduce cytotoxic gene expression in immune cells. So killing activity of immune cells become weak. It can also promote formation of suppressive Tregs.

Tumor cells and surrounding stromal cells secrete suppressive cytokines. Important cytokines are TGF-β, IL-10, and VEGF. These molecules inhibit effector immune cells and support abnormal blood vessel growth.
Tumors recruit suppressor cells into tumor area. These cells include Tregs, myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). These cells suppress natural anti tumor immunity.

Cancer Immunoediting

Cancer immunoediting is a process where immune system has two type role in cancer. It protects the body by destroying tumor cells. At the same time it also gives selection pressure on tumor cells. So only more resistant tumor cells can survive.

In this process the immune system acts as tumor suppressor. It recognize abnormal cells and remove them. But during long interaction, it also shape the tumor. This makes tumor cells less immunogenic and more able to escape immune attack.
The process of cancer immunoediting occurs in three phases. These are elimination, equilibrium, and escape.
Elimination phase is also called immune surveillance. In this phase, innate immunity and adaptive immunity work together. They detect transformed cells before they form clinically visible tumor mass.

T cells, natural killer cells (NK cells) and dendritic cells are important in elimination phase. These cells attack abnormal tumor cells. They use perforin, cytotoxic molecules and cytokines to destroy the transformed cells.
Equilibrium phase occurs when some tumor cells survive after elimination phase. In this phase, tumor cells remain in dormant condition for long time. The adaptive immune system keeps their growth under control.
During equilibrium phase, tumor cells remain under continuous immune pressure. This pressure is not always killing all tumor cells. It is sub-lethal pressure. Due to this, tumor cells undergo genetic and epigenetic changes.

In this phase, tumor variants with reduced immunogenicity are selected. These tumor cells express less recognizable antigens. So they are less detected by immune cells. This is the editing part of immunoediting.
Escape phase occurs when edited tumor cells overcome immune control. These cells grow continuously. Then they form clinically detectable cancer.
In escape phase, tumor cells make immunosuppressive condition around them. This area is called tumor microenvironment. It helps tumor cells to avoid immune destruction.

Tumor cells may downregulate tumor antigens and MHC molecules. Due to this, cytotoxic T cells cannot recognize tumor cells properly.
Tumor cells also cause T cell exhaustion. Exhausted T cells lose their proper killing activity. So the anti tumor response become weak.
Tumor also recruits suppressor immune cells. These include regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). These cells suppress anti tumor immune response.

Role of Cytokines in Tumor Immunity

Tumor killing– Cytokines help in direct destruction of tumor cells. Cytotoxic CD8+ T cells and CD4+ Th1 cells release these cytokines during anti tumor reaction.
- IFN-γ can inhibit tumor cell growth. It may push tumor cells into senescence and permanent cell cycle arrest.
- TNF-α helps in tumor cell damage and tumor cell killing. It also support inflammatory reaction around tumor.

Early activation– Type I interferons (IFN-α/β) are important in early anti tumor response. They activate immune cells and make tumor cells more visible.
- They activate dendritic cells.
- They increase antigen cross-presentation.
- They promote T cell priming and survival.
- They activate natural killer cells (NK cells).
- They increase MHC-I expression on tumor cells.
Th1 formation– Interleukin-12 (IL-12) helps in formation of Th1 phenotype from CD4+ helper T cells. This is pro-inflammatory type response. It also increase tumor killing activity of cytotoxic T lymphocytes and NK cells.
Cell survival– Interleukin-15 (IL-15) helps in proliferation and survival of T cells and NK cells. It prevents early death of these immune cells. So anti tumor immunity remain active for longer time.

Immune recruitment– Interleukin-1β (IL-1β) induce production of chemokines. These chemokines act like chemical signal for immune cells.
- CCL2 recruits immune cells to tumor area.
- CXCL1 also helps in rapid movement of immune cells toward tumor site.
Tumor dormancy– In equilibrium phase, some tumor cells are not eliminated completely. These tumor cells remain in dormant condition. This is maintained by balance between anti tumor cytokines and tumor promoting cytokines.
- IL-12 and IFN-γ keep tumor growth under control.
- IL-23 and IL-10 may support tumor cell survival and tumor growth.
Immune suppression– Tumor cells and hijacked immune cells release suppressive cytokines. These cells include regulatory T cells (Tregs) and M2 macrophages. These cytokines suppress anti tumor immune response.
- TGF-β suppress T cell activity and help immune tolerance.
- IL-10 reduce inflammatory response and antigen presentation.
- IL-35 suppress effector immune cells and support tumor escape.
Angiogenesis– VEGF is released by tumor cells. It helps in formation of abnormal new blood vessels. These vessels supply nutrient and oxygen to tumor. VEGF also form barrier, so effector immune cells cannot properly enter into tumor core.

Dual role– Cytokines have both anti tumor and pro tumor role. IFN-γ, TNF-α, IFN-α/β, IL-12, and IL-15 support tumor immunity. But TGF-β, IL-10, IL-35, IL-23, and VEGF help tumor escape and growth.

Tumor-Induced Immunosuppression

Metabolic starvation– Tumor cells consume very high amount of glucose by aerobic glycolysis. This is also called Warburg effect. Due to this, effector T cells become starved. Their activity become weak and exhausted.
Acidic microenvironment– Tumor cells release high level of lactate. So tumor area become acidic. This acidic condition paralyze attacking T cells and dendritic cells. It also support Tregs and change macrophages into M2 phenotype.

Toxic metabolites– Tumor microenvironment has accumulation of lipids, kynurenine, and branched-chain keto acids (BCKAs). These metabolites directly suppress immune cells. They reduce macrophage phagocytosis and produce T cell anergy.
Suppressor cells– Tumors attract and increase suppressive immune cells in tumor area. Mainly regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and M2 tumor-associated macrophages (TAMs) are involved. These cells suppress natural anti tumor response by contact, nutrient depletion and cytokines.
Suppressive cytokines– Malignant cells and surrounding stroma release TGF-β, IL-10, and VEGF. These cytokines suppress immune cell function. They also block effector immune cells from entering into tumor tissue.

Innate checkpoints– Tumor cells express don’t eat me signals on their surface. Important signals are CD47-SIRPα axis and CD24-Siglec-10 axis. These signals bind with macrophages and give inhibitory signal. So tumor cells are not engulfed and destroyed.
Physical barrier– Tumors produce excess collagen fibers and cross-link them. It makes dense and stiff matrix around tumor. This matrix traps dendritic cells and cytotoxic T cells in surrounding stroma. So they cannot reach tumor core.
Matrix stiffness– The stiffness of tumor matrix acts as mechanical force on immune cells. It prevents dendritic cell maturation and disturb T cell activation. It may silence cytotoxic molecules like IFN-γ and causes long lasting T cell exhaustion through LAIR1 receptor.

Antigen hiding– Tumor cells may downregulate or lose their tumor antigens. They also reduce MHC class I molecules. So cytotoxic T lymphocytes cannot recognize tumor cells. This makes tumor invisible to adaptive immunity.
Final effect– By these mechanisms tumor makes suppressive condition around it. Immune cells become weak, blocked and exhausted. So tumor escapes from immune response and grow continuously.

Immunological Markers of Tumors

Tumor-associated antigens– Tumor-associated antigens (TAAs) are normal host proteins. These are over expressed or abnormally expressed in tumor cells. These are also present in normal cells, but in tumor they are present in high amount. Examples are WT1, Her2/neu, MUC1, and carcinoembryonic antigen (CEA).

Tumor-specific antigens– Tumor-specific antigens (TSAs) are also called neoantigens. These are present only in tumor cells. They are absent from normal healthy tissues. These antigens are formed due to somatic mutation or oncogenic viral proteins. So they act as highly specific marker of tumor.
Cancer/testis antigens– Cancer/testis antigens (CTAs) are normally present in male germline cells of testis. These cells are immune privileged. But in many cancer, these antigens are re-expressed abnormally. Important CTA markers are MAGE family, MAGE-A1, MAGE-A3, NY-ESO-1, PRAME, and SSX.
DAMPs– Danger-associated molecular patterns (DAMPs) are danger signals. These are released or exposed when tumor cells undergo immunogenic cell death (ICD). These signals recruit and activate immune cells in tumor area.
- Calreticulin (CRT) appears on tumor cell surface. It acts as eat me signal for dendritic cells and macrophages.
- Adenosine triphosphate (ATP) is secreted outside the cell. It acts as find me signal and attract immune cells to tumor site.
- High-mobility group box 1 (HMGB1) is released from dying tumor cells. It binds with receptors like TLR4 and helps in dendritic cell maturation.

Immune checkpoint proteins– These are surface proteins used by tumor cells to suppress immune response. PD-L1 is an important checkpoint marker. It binds with receptor on T cells and causes T cell exhaustion. So active anti tumor response become weak.
Don’t eat me signals– These are innate immune escape markers present on tumor cell surface. Important markers are CD47 and CD24. These proteins give inhibitory signal to macrophages. So macrophages do not engulf and destroy tumor cells.
Main importance– These markers help in identification of tumor cells and tumor immune condition. Some markers help immune system to recognize tumor. Some markers help tumor to escape immunity. So they are important in tumor diagnosis and cancer immunotherapy.

Tumor Immunotherapy

Tumor immunotherapy is a cancer treatment method in which body’s own immune system is used to recognize and destroy tumor cells. It boost anti tumor immunity and make immune cells active against malignant cells.

Types of Tumor Immunotherapy

Checkpoint inhibitors– These are antibody drugs which block immune brake signals used by tumor cells. Main targets are PD-1, PD-L1, and CTLA-4. After blocking these signals, T cells become active and attack tumor cells.
Adoptive cell transfer– In this method, patient’s own T cells are taken out and modified or expanded in laboratory. Then these cells are given back to patient. Important types are CAR-T cell therapy and TCR-T cell therapy.

Cancer vaccines– These vaccines are used to treat existing cancer. They contain tumor markers such as neoantigens or cancer/testis antigens (CTAs). These antigens activate dendritic cells and stimulate tumor specific T cell response.
Oncolytic virotherapy– This therapy uses natural or modified viruses to infect and lyse tumor cells. Examples are modified Herpes simplex virus-1, Adenovirus, and Coxsackievirus. Tumor cell lysis release DAMPs and make immune response active.
TME modulators– These therapies target tumor microenvironment. They break dense collagen matrix and metabolic barriers around tumor. Examples are LOX inhibitors, FAK inhibitors, and TGF-β blockers. So cytotoxic T cells can enter tumor core.

Clinical Significance of Tumor Immunology

Cancer diagnosis– Tumor immunology helps in detection of cancer by identifying tumor antigens and immune markers. Markers like CEA, Her2/neu, MUC1, MAGE, and NY-ESO-1 are used in different tumor study. These markers help to know presence and nature of tumor.
Tumor classification– Different tumors show different antigenic characters. So immunological markers help in classification of tumor. It helps to separate one tumor type from another tumor type. This is useful in diagnosis and treatment planning.
Prognosis– Tumor immunity also gives idea about disease outcome. Presence of high cytotoxic T cells in tumor area usually indicate better immune control. More Tregs, MDSCs, and M2 macrophages usually indicate poor anti tumor response and bad prognosis.

Immunotherapy development– Tumor immunology is the base of modern cancer immunotherapy. It helps to develop treatment like checkpoint inhibitors, CAR-T cell therapy, cancer vaccines, and oncolytic virus therapy. These treatments use immune system against tumor cells.
Checkpoint therapy– Study of PD-1, PD-L1, and CTLA-4 has clinical importance. These molecules suppress T cell activity in cancer. Blocking these checkpoints can restore T cell function and help in tumor killing.
Vaccine design– Tumor antigens are used for making cancer vaccines. Neoantigens, tumor-associated antigens, and cancer/testis antigens can stimulate tumor specific immune response. This helps in targeted cancer treatment.

Monitoring treatment– Immune markers are used to observe response of patient during therapy. Changes in T cell activity, cytokines and tumor antigen level can show whether treatment is working or not. It helps in follow up of cancer patient.
Personalized medicine– Tumor immunology helps to select treatment according to patient tumor profile. Tumor antigen, mutation and immune checkpoint expression are studied. Based on this, specific immunotherapy can be selected.
Understanding immune escape– It helps to know how tumor cells escape immune attack. Tumor may reduce MHC class I, hide antigen, produce TGF-β, IL-10, and recruit suppressor cells. This knowledge helps to make better treatment combination.

Minimal residual disease– Immune system can recognize small number of remaining tumor cells after treatment. This is important for preventing recurrence. Strong anti tumor immunity may control residual cancer cells.
Combination therapy– Tumor immunology helps in combining immunotherapy with chemotherapy, radiotherapy or targeted therapy. Some treatment increase antigen release and immune activation. So combination therapy may give better result.

Limitations of Tumor Immunotherapy

Low response rate– Tumor immunotherapy does not work in all cancer patients. It gives benefit only in some group of patients. Many tumors show primary resistance or acquired resistance after treatment.

Cold tumors– Some tumors are called immunologically cold tumors. These tumors have very low T cell infiltration. So checkpoint inhibitors or other immunotherapy cannot work properly because active immune cells are already absent in tumor area.
Physical barrier– Solid tumors make dense and stiff extracellular matrix around them. This matrix is highly cross-linked. It blocks immunotherapeutic drugs and also traps CAR-T cells in surrounding stroma. So these cells cannot enter tumor core.
Metabolic starvation– Tumor cells consume large amount of glucose. So attacking T cells and dendritic cells do not get enough nutrient. These immune cells become weak and exhausted.

Acidic toxicity– Tumor cells release high amount of lactic acid. This makes tumor area acidic. This acidic microenvironment suppress immune cell activity and cause T cell anergy.
Antigen loss– Tumor cells may lose or reduce their target tumor antigens. They may also downregulate MHC class I molecules. So targeted immunotherapy cannot recognize tumor cells properly.
Autoimmune toxicity– Therapies against tumor-associated antigens (TAAs) may also attack normal tissues. Because these antigens are also present in low amount on healthy cells. This can cause off-target autoimmune reaction.

Suppressor cells– Tumors recruit Tregs, MDSCs, and M2 macrophages. These cells suppress active anti tumor immune response. They inhibit T cells, NK cells, and antigen presenting cells.
Don’t eat me signals– Tumor cells express CD47-SIRPα and CD24-Siglec-10 signals. These signals prevent macrophage phagocytosis. So tumor cells are not engulfed and destroyed.
Intracellular antigens– Many tumor antigens are present inside cytoplasm of tumor cells. They are not exposed on cell surface. So antibody based therapy and CAR-T cell therapy cannot easily bind with these antigens.
Virus clearance– In oncolytic virotherapy, therapeutic virus may be neutralized by host immune system. Pre-existing antibodies may also clear the virus. So virus cannot reach tumor cells and lyse them properly.
Vaccine difficulty– Cancer vaccines are difficult to prepare. Many vaccines need personalized antigen selection. Their production is costly and complex. They may also fail to produce strong and long lasting immune response.

Advantages of Tumor Immunotherapy

Targeted response– Tumor immunotherapy produces more specific immune response against tumor cells. It can attack malignant cells with less damage to normal tissues. So collateral damage is less than chemotherapy and radiotherapy.
Low toxicity– Some modern immunotherapy like mRNA cancer vaccines show low toxicity. They do not need to enter into cell nucleus. So there is no risk of insertional mutagenesis.
Long-term protection– Immunotherapy can form immunological memory. Memory immune cells remain in body for long time. They can recognize same tumor antigen again and help to prevent cancer recurrence.
Tumor adaptation– Immune system can adapt against changing tumor cells. Tumor cells mutate continuously. But immune response can develop new specificity against new tumor antigens. So it can act against genetically unstable tumor.
Cellular immunity– Some immunotherapy activate T cell mediated immunity. Cytotoxic T cells recognize tumor antigen and destroy tumor cells. This is important for killing of intracellular and solid tumor cells.
Humoral immunity– Some immunotherapy also stimulate B cells and antibody response. mRNA cancer vaccines may induce both cellular and humoral immunity without extra adjuvant.
Cold to hot tumor– Some therapies can convert immunologically cold tumor into hot tumor. Oncolytic viruses lyse tumor cells and release danger signals. This makes tumor area inflamed and attract tumor killing immune cells.
Tumor microenvironment change– Immunotherapy can reverse suppressive tumor microenvironment. It can increase immune cell entry and reduce immune silence in tumor area. So tumor become more responsive to immune attack.
Rapid production– Some therapies like mRNA vaccines can be produced faster and in scalable way. Their manufacturing is easier and efficient. So treatment can be made according to patient specific tumor antigen.
Stable disease– Immunotherapy may cause complete tumor regression in some patients. In other cases, it may keep tumor growth under control and produce stable disease for longer time.

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Tumor Immunology – Definition, features