Tumor Immunity Flashcards
Immune Surveillance
Evidence supporting the concept of immune system reacts against tumors
Diminished T cell function?
Control and elimination of malignant cells by immune system
A) Lymphocytes infiltrate some tumors b) Immunocompromised with diminished T cell function have higher incidences of lymphoproliferative cancers
CD4 T cells can’t secrete cytokines that activate macrophages
CD8 T cells no CTL mediated tumor eradication
Tumor rejection is mediated by
Types of Tumor Antigens
Lymphocytes
TSA: tumor specific antigen: arise from mutations or oncogenic transformation, tumor specific endogenous retroviruses (TSERVs)
TAA: tumor associated antigen: present in tumor and normal cell. Overexpression of normal proteins, tissue specific gene patterns, or expression of proteins derived from gene expression restricted to testes (germline)
Tumor Antigens types
Neoantigens generated by mutations unrelated to tumorigenesis
Aberrantly expressed normal proteins eg Cancer/testis antigens in many tumors
Amplified genes over-expressed normal proteins HER2 breast cancers
Normal proteins expressed by tissue of tumor origin eg Tyrosinase in melanoma; CD20 on B cell lymphomas
Protein antigens expressed by oncogenic virus eg EBV (EBNA), HPV (E6, E7)
HER2/Neu as example of tumor antigen that results from over expression cellular protein
It is duplicated amplified in some breast cancer cells
EGF binds EGF promotes cell proliferation
TRASTUZUMAB USED IN TREATMENT
Oncofetal Ag/Carcinoembryonic Antigen (CEA)
Ag/alpha Fetoprotein (AFP)
High conc disappear at birth and reappear in serum with colerectal cancer
Circulating glycoprotein normally synthesized and liver in fetal life; Low levels: typical adults High levels: fetal
How does the Immune system fight Cancer
Release cancer antigens—>presentation of cancer cell antigens—>priming and activation—>trafficking of T cells to tumors—> infiltration of T cell into tumors—> Recogn of cancer cells by T cells—> Killing of cancer cells
Innate Immune System - Macrophages
M1 macrophages promotes tumor suppression: IFNg—>respiratory burst, NO release, TNF a and ADCC
M2 macrophages promote tumor growth: secrete IL10 & TGFB—> promote T reg differentiation—> suppress differentiation of Th1 and CTL cells—> secrete cytokines that augment tumor growth (VEGF) stimulates angiogenesis
NK cells
Kill many types of tumor cells esp those with low MHC 1 expression
ADCC (antibody dependent Cell Mediated Cytotoxicity) and lysis
IL12, IL15 and IFNg increase NK cytolytic activity
CD8 T cell response against tumors (MOST PIVOTAL)
Perform immune surveillance function by recognizing and killing potential malignant cells that express peptides derived from tumor antigens and are presented in association with class I MHC molecules
1) Perforin/granzme mediated cell killing; Perforin induces uptake of granzymes into target cell endosome and release into cytosol activating caspases CTL releases granule contents into immune synapse
2) FAS/FASL mediated cell killing
CD4 T cell against Tumors and Antibodies
Secrete IL2 to activate CTLs
Secrete IFNg which activates macrophages (M1) —> increase expression of M1
Mediate antibody cell-mediated cytotoxicity (ADCC) in which Fc receptor bearing macrophages or NK cells mediate the killing
How do Tumors Evade Our Immune response
Immunosuppressive tumor environment
Loss of tumor antigen expression
Inhibition of tumor infiltration by T cell - Down regulate of MHC expression
Inhibit T cell activation - down-regulate of costimulation, increase CTLA 4 and PD1, secrete immunosuppressive cytokines TGFB and IL10
Reduced activation of dendritic cells - lack of costimulation
Cancer Immunotherapy
Cytokine
Monoclonal antibodies
Checkpoint inhibitors
Cancer Vaccines
ACT
Oncolytic Virus
Adoptive T cell therapy
Autologous Adoptive : T cells harvested from pat blood—> grown in culture to increase number —> transferred back to blood
Adoptive transfer of CAR T cells: T cells harvested from pat blood—> grown in culture to increase number —> transfected with genes coding for chimeric receptor with specificity to patient’s tumor antigens—> transferred back to blood
Chimeric Antigen Receptor T cell (CAR Tcell)
Used successfully on patients with leukemias
Determine tumor antigens and genetically engineer appropriate receptors—> isolate patients CD8 —> transfect with recombinant gene containing antigen receptor and signal domains
CART receptor: Variable regions of IgG(enable T cell binding to tumor)
Transmembrane portion of IgG
Signaling domains of both TCR and Costimulatory molecules (enables signal generation to activate killing mechanism)
Monoclonal Antibodies are produced from a clone of antibody producing cells
Hybridoma-immortalized cell fusion of B cell and myeloma cell
Each cell makes identical antibodies
Examples
Anti CD20 Rituximab for B cell lymphomas
Brentuximab vedotin for Hodgkins lymphoma
Transtuzumab targets epidermal growth factor receptor for HER2/Neu found on 1/6 breast cancer acts to inhibit growth
Blanatumomab - Chimeric Monoclonal with specificity for CD19 and CD3
