CD8+ T cell exhaustion Flashcards
What is the effect of hypoxia on T cells?
- A less efficient activation by TCR derived signals and costimulation
- HIF1a deficient T cells respond with higher intensity to stimulation of the antigen receptor
- Functional advantage of T cells upon conditional deletion of the HIF1a gene in T cells –> CD4 and CD8 HIF1a deficient T cells showed a more intensity ability to proliferate and produce IFNg
- Hypoxia leads to less efficient target killing by CTLs
- T cell activation under hypoxia leads to up regulation of CD137 upon antigen stimulation–> mechanisms dependent on HIF1a
Mechanisms involved in hypoxia mediate T cell immunosuppression?
- Release of adenosine (endogenous purine nucleoside) to the extracellular space, which acts on A2R inhibitory receptors –> cAMP
- Production of oxygen free radicals–> inhibit NFkB translocation into nucleus –> switch off cytokine production; selective degradation of TCR components
- HIF1a control of genes that down modulate the immune response: favors differentiation of Th17 cells via direct transcriptional regulation of RORgt (partners with phosphorylated STAT3); recruits ubiquitination machinery to degrade FOXP3
- Inhibits lymphocyte expression of IL-2 and proliferation
- Apoptosis in Jurkat T cells
Indirect effects of hypoxia on immunosuppression of TILs?
- Hypoxic tumor cells produce high levels of chemokine CCL28–> selectively attracts Tregs that express CXCR10–> antigen tolerance + angiogenesis
- Under hypoxia, tumor cells activate autophagia –> protects malignant cells from being killed by T cells
- Inhibited maturation and migration of DCs, which affected T cell activation and function
How does adenosine accumulation induce immunosuppression of T cells?
Binding of adenosine to the G-coupled protein receptor; T cells predominantly express A2aR and A2bR –> inhibits adhesion on T cells and cytotoxic activity
Adenosine signaling pathway is associated with T cell survival: deficiency in adenosine deaminase (purine catabolic pathway) –> apoptosis of CD8 low transitional and CD4+CD8+ thymocytes
Hypoxia upregulates A2aR on T cells, which leads to CCR7 inhibition –> CCR7 is no longer able to protect T cells from apoptosis
Generation of anti-tumor T cells?
- Antigen uptake and processing by APCs in the tumor: mutational neoantigens, non mutated genes over expressed by cancer cells, differentiation antigens related to cancer’s tissue of origin.
- Lymph node homing
- T and NK cell activation
- T and NK cell recruitment
- Tumor Cell Killing
Generation of tumor reactive T cells?
- Defective DC function –> deregulation of DC maturation
- partially mature DCs: intermediate amounts of MHCI and II costimulatory molecules; high amounts of coinhibitory molecules; immunossupressive cytokines
- unable to elicit antigen-specific T cells –> anergy of effector T cells and/or expansion of Tregs
- VEGF; PDL-1; tumor-derived soluble factors: TGFb, IL-10, M-CSF, IL-6;
- IL-10 induces PDL-1 expression on DCs
- HYPOXIA can influence DC phenotype and function
- IDO and PGE2
- Properly mature DCs that express costimulatory ligands might be important at the tumor site to maintain an effective CD8+ T cell function
Reaching the tumor site?
- Disruption of normal chemokines
- Tumors with high numbers of T cells express high amounts of T cell attracting chemokines : CCL2, CCL3, CCL4, CCL5, CXCL9, CXCL10
- A few T cells infiltrate the tumor environment initially followed by a large influx of both specific and nonspecific T cells
- Skin tumors: aberrant EGFR-Ras signaling suppresses CCL27 (expressed by normal keratinocytes) –> prevented T cell homing and accelerated tumor growth
- Aberrant post-translational modifications –> altered activities of expressed chemokines; e.g. CCL2 undergoes nitrosylation induced by ROS –> abrogates CCL2’s ability to attract CTLs but it can attract MDSCs
- Altered proteolytic processing –> e.g. CXCL11
Crossing tumor vasculature?
- Type and quantity of adhesion molecules expressed - maintained by soluble tumor factors
- Angiogenic molecules (VEGF) inhibit adhesion molecule expression on endothelial cells
- TNFa induced T cell adhesion is minimal / unable (in the presence of VEGF) to induce expression of ICAM1 and VCAM-1
- Endothelins: interact with VEGF –> inhibitory factors (nitric oxide)
- Tumor vasculator via mechanisms independent of adhesion molecules: FasL , TNF-related apoptosis inducing ligand (TRAIL), CD31, immunossupressive soluble molecules
Negotiating tumor stroma space and suppressive leukocytes
Tregs/MDSCs
- nTregs = derived from the thymus and maintained peripherally by TGFb
- iTregs = induced from naive CD4+ T cell precursors
- Secrete soluble mediators: TGFb, IL-10, IL-35 –> suppress T cell expansion and cytokine production
- Require IL-2 support –> IL-2 sink –> starving effector CTLs
- Directly kill T cells via cytolysis mediated by TRAIl and granzyme B
- Engage in crosstalk with DCs –> induce expression of IDO, IL-10, TGFb
- HYPOXIA exposed Tregs are more effective at inhibiting proliferation of effector T cells
MDCS: produce arginase I and ROS, IL-10, and TGFb
- Can expand Tregs in the tumor environment
- HYPOXIA increases expression of BV8 and CXCL12 –> recruitment of MDSCs; enhanced blood vessel development;
The encounter with tumor cell?
T cells depend largely on recognition of targets through MHC-TCR interaction
- Evasion mechanisms by loss of expression or down regulation of the antigen-presenting machinery
- Tumors express molecules that can directly kill T cells : FasL and TRAIL
- Express surface proteins such as PD-L1, PD-L2, and B7-H4 which suppress T cell function and arrest tumor rejection
- Toxic environment for optimal T cell function; soluble mediators TGFb, IL-10, PGE2, histamine, hydrogen peroxide, and adenosine
- Deprivation of metabolic substrates
- Low extracellular pH
Therapies to Restore anti-tumor immunity?
- Endogenous immune response is entirely paralyzed or ineffective
- Effective tumor cells can be expanded ex vivo from natural TILs or from T cells transducer with endogenous cloned TCRs or chimeric antigen receptors (CARs)
- Host can be conditioned by lymphodepletion –> optimize engrafment
- Endogenous T cells can be effectively activated by pharmacological checkpoint inhibitors
- Vasculature can be disrupted by low-dose metronomic chemotherapy or normalized by drugs targeting angiogenesis
- Individual blockade of soluble inhibitory factors
- Exogenous vaccines
- Activation of tumor-associated antigen presenting cells by drugs
Tumors with pre-existing TILs?
CTLA-4: potent negative regulator of T cell activation –> binds to members of B7 family of costimulatory molecules
PD-1: enhance of T cell responses in vitro and in vivo in preclinical tumor models;
Bispecific antibodies: activation of TILs in a nonspecific manner
Tumors without pre-existing TILs?
Immune escape might be caused by down regulation of antigen-presenting machinery in tumor cells, e.g. epigenetic deregulation - can be reversed with histone deacetylase inhibitors or low IFNg levels
The Cancer Immunity Cycle?
- Release of cancer cell antigens (cancer cell death)
- Cancer antigen presentation: DCs and APCs
- Priming and activation of T cells (LN)
- Trafficking of T cells to tumor (CTLs)
- Infiltration of T cells into tumor
- Recognition of cancer cells by T cells
- Killing of cancer cells
- A common rate-limiting step is the immunostat function, immunosuppression that occurs in the tumor microenvironment.
Initiating anti-cancer immunity: antigen release, presentation, T cell priming
Vaccines
- Negative signals in the tumor microenvironment may dampen or disable anti-tumor responses before clinically relevant killing has occurred
- Identification of proper tumor antigens
- Configuring multi-valent vaccines
- Difficult to identify MHC I - bound peptides that could selectively target T cell responses to
- Delivery of antigens
- Assessing the naturally occurring source of cancer antigen
