Tumor immunology/Cancer immunology

The tumor immune microenvironment plays a critical role in cancer progression, metastasis, and therapeutic response.

The immune system is constantly auto regulating between pro inflammatory and anti-inflammatory states globally and focally within malignant deposits.

Advanced cancer causes immune suppression and an immunosuppressed state can pre-dispose to cancer.

Malignancies use various mechanisms to evade antitumor responses.

Tumor cells down regulate major histocompatibility complex expression, reducing their presentation to the immune system.

Some tumors attract myeloid derived suppressor cells that interfere with their maturation, reducing antitumor immunity.

Regulatory T cells dampen immune responses against tumors.

Malignancies use breaks of the immune system such as programmed cell death 1 and cytotoxic T-lymphocyte-associated protein 4, to turn down immune responses.

When the immune system recognizes a tumor, it destroys the cells that it can from the tumor and forms the elimination phase, also called the phase of immune surveillance.

The tumor cells that escaped the initials immunosurveillance enter a phase of equilibrium, during which the cells undergo mutations to evade immune response.

Such tumor cells undergo cancer immunoediting where they are altered to bypass immune killing cells.

By the time tumor Cells enter the escape phase they have enough mutations to elude the immune system and grow unchallenged.

An effective antitumor response requires recognition of tumor specific proteins called neo-antigens, induction of the body’s innate and adaptive immune machinery, effective migration of the key immune cells into the tumor deposits, and maintenance of the attack at the tumor-immune cell interface.

Most cancer cells are initially recognized by the immune system, specifically cytotoxic CD8 positive T cells, as foreign or abnormal protein production from DNA mutations, that lead to the neo antigens.

Most malignant cells are initially immunogenic, recognized and destroyed by the immune system before forming clinically detectable tumors.

Two major cytolytic mechanisms of the adaptive immune system include the antibody-dependent, cell mediated cytotoxicity (ADDCC) and killing by CD8+ cytotoxic T lymphocytes (CTLs).

Antibody-dependent, cell mediated cytotoxicity promotes tumor cell killing when specific antibodies recognize and bind to surface structures on tumor cells.

ADDC facilitates the Fc mediated activation of natural killer cells.

CD8+ cells and cytotoxic T lymphocytes recognize tumor antigen peptides in class I major histocompatibility (MHC) molecules, through their T cell receptor antigen.

Optimal T-cell activation requires signal 1 the recognition of the cognate peptide major histocompatibility complex (MHC) by a specific T-cell receptor and signal 2, which is ligation of the CD28 costimulatory receptor by its ligand B7.1/B7.2 (CD80/CD86).

Immunotherapy attempts to modulate the host’s tumor directed immune response, produces a novel antitumor immune reaction, or provides the patient with an active anti tumor immune effector cells.

The host’s immune response can be modulated by enhancing functional immunogenicity by overcoming mechanisms which weaken responses to tumor associated antigens, such as interruption of T-cell down regulatory pathways that contribute to immune tolerance.

The protein based tumor antigens are released by the tumors and taken up by dendritic cells where they are cleaved by proteases to peptides that associate with major histocompatibility complex (MHC) molecules.

Cancer immunolgy and immuno editing involves elimination of tumor cells by the innate immune system such as natural killer cells and by the adaptive immune system such as by effector CD4+ and CD8 positive T cells.

Cancer immunotherapy types are passive immunotherapy using components of the immune system to direct targeted cytotoxic activity against cancer cells without necessarily initiating an immune response, while activity actively triggers an endogenous immune response.

The development of CTLA-4, PD-1/PD-L 1, and LAG-3 inhibitors have expanded cancer treatment options.

As of March 2023, there are 11 approved immune checkpoint inhibitors.

Passive cancer immunotherapy includes the use of monoclonal antibodies produced by the cells in response to a specific antigen.

The MHC system picks up the peptides and traffics them to the surface of the cell, where T cells recognize the peptide-MHC complex.

T cell activation requires two signals: the first signal is the binding of the T cell receptor (TCR) to a tumor peptide presented by the major histocompatibility complex (MHC), and the second is the full T-cell activation, TCR-MHC peptide interaction must be accompanied by the binding of CD 28 on T cells to the costimulatory molecules CD 80 CD86 both members of the B-7 family on the surface of the antigen presenting cell.

T-cell stimulation results in proliferation of T cells and initiates cytokine secretion release of granzyme B and perforin needed for cell killing.

Recognition of tumor antigens requires uptake by phagocytic cells such as dendritic cells which process them into fragments which are assembled into major histocompatability complex (MHC) molecules-class I and class II for cell surface presentation to CD8 T cells and CD4 T cells, respectively.

Cancer cell immunogenicity changes over time, referred to as immunoediting.

The less immunogenic cancer cells will overcome the immune system leading to clinically detectable and immuno resistant tumors.

CD4+ and CD8 + lymphocytes are activated by at least two signals between T. lymphocytes and antigen-presenting cells, known as been dendritic cells: The first signal occurs between major histocompatibility complexes and T-cell receptors to present the specific antigen, And the second signal is generated by binding of CD 28 receptor on T cells to B7-1 and B7-2 molecules on antigen presenting cells.

CTLA-4 is expressed on surface of T cells within 2 to 3 days following activation.

Highly immunogenicity tumor and evidence of immune response to cancer are often correlated with better prognosis.

T-helper cells subsequently produce a number produce cytokines including IL-2 that propagates the immune response.

Lymphocytic infiltrates in cancer tissue is associated with improved prognosis, suggesting the immune system participates in eradication of tumor cells, and the control of tumor growth.

In the Breast Internation Group (BIG) trial triple negative BC, an increased lymphocytic infiltrate was associated with a reduced relapse rate and improved survival, independent type of chemotherapy, and was not observed in hormone receptor positive tumors.

The presence of tumor associated lymphocytes in breast cancer patients is an independent predictor of response to neoadjuvant chemotherapy suggesting a pre-existing immunologic response may enhance the effects of conventional cytotoxic chemotherapy (Denkert C).

Dendritic cells express costimulatory molecules that bind to receptors in the T cell.

The B7 molecule is highly expressed by dendritic cells, and the receptor for the B7 molecule on the cells is the CD28.

Signal 1 through the T cell receptor and signal 2 through CD28 activates the T cell as presented by the dendritic cells.

Tumor cells produce cytokines that can break the dendritic cell activation cycle preventing immune responses.

IL-6 and IL-10 are cytokines produced by tumors that can inhibit dendritic cell function.

Tumors consist of malignant cells and stromal cells plus infiltrating lymphocytes and the later play a role in regulating tumor progression via immune mechanisms angiogenesis and tissue remodeling.

High frequency of tumor infiltrating lymphocytes (TILs) correlates with favorable outlook.

Myeloid cell infiltration of tumors is associated with a poor prognosis with increased levels of angiogenesis, tissue remodeling and impaired ant tumor immunity.

Can induce aberrant myelopoiesis.

Cytotoxic T- lymphocyte antigen-4 (CTLA-4) is a key negative regulator of immune responses.

CTLA-4 plays in important role in preventing auto immunity by preventing excessive T cell activation.

Tumor cells escape recognition and destruction by the immune system by dysregulating immune cell activity of T cells and NK cells.

Tumor cells can activate T-cell inhibitory, checkpoint, pathways such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death-1 (PD-1) and lymphocyte antigen gene (LEnclosure uncleHystericalAG-3), inhibition of T-cell activation pathways such as CD137, OX-40, CD as well as married40, GITR, HVEM and suppression of NK cell activity.

CTLA-4 monoclonal antibiotibodies suppress inhibitory receptors on T cells to help destroy tumors.

The microenvironment may support T-cell infiltration and antitumor immune response.

The extent of hyper mutation within the tumor may predict a better response to immunotherapy because mutations generate neoadjuvant antigens which may trigger anti tumor immune response.

Vaccines are active immunotherapy, and most present specific tumor antigens to the immune system and provide immune modulation to allow a maximum response.

Sipuleuce-T is the first and only approved therapeutic cancer vaccine.

Adoptive cell transfer of tumor infiltrating lymphocytes is a passive immunotherapy used primarily in metastatic melanoma.

Active immunotherapy has the potential to provide long-lasting anticancer activity by engaging in both the innate and adaptive arms of the immune response.

Monoclonal antibodies are considered passive immunotherapies but there is however evidence that they also induce adaptive immune responses via vaccination like effect.

There are 3 main mechanism by which cancer cells may evade the immune system:

The tumor may lose expression of key immunogenic neoantigens as well as the MHC complex which is required for recognition by cytotoxic cells.

Tumor cells can also produce suppressive cytokines and express checkpoint proteins like PD-L1 that blunt the immune response.

Also cytokines like VEGF can affect the microenvironment and drive faulty angiogenesis leading to poor tumor blood flow and suppress immune cell tracking.

Cytotoxic T cells and macrophages may shift phenotypes through expression of checkpoint proteins, evolution to an anergic state, or become T regulatory cells.

Cancer cells can evade immune system recognition by 3 main mechanisms: immunoediting cells so that they lose expression of key immunogenic neoantigens, cancer cells can produce immunosuppressive cytokines that express checkpoint proteins that blunt the immune response, and tumor T cells and macrophages may express checkpoint proteins that shut down for that activation, evolve into an anergic state, or become suppressive phenotypes.

The administration of monoclonal antibodies (mAbs) is a form of passive 

Immunotherapy.

Monoclonal antibodies  facilitate destruction of tumor cells by complement-dependent cytotoxicity (CDC) and cell-mediated cytotoxicity (ADCC). 

In complement-dependent cytotoxicity , the monoclonal antibody binds to specific antigen, leading to activation of the complement cascade, which in turn leads to formation of pores in tumor cells. 

In cell-mediated cytotoxicity (ADCC) the Fab domain of a mAb binds to a tumor antigen, and Fc domain binds to Fc receptors present on effector cells, which are phagocytes and NK cells, thus forming a bridge between an effector and a target cells. 

This induces the effector cell activation, leading to phagocytosis of the tumor cell by neutrophils and macrophages. 

Furthermore, NK cells release cytotoxic molecules, which lyse tumor cells.