2.3 Tumor Immunology, Antigen Presentation & Mechanisms of Immune Evasion
Key Takeaways
- The anti-tumor immune response proceeds through the 7-step Cancer-Immunity Cycle (Chen & Mellman), from immunogenic antigen release and dendritic cell cross-presentation to T-cell trafficking, tumor infiltration, TCR-MHC recognition, and perforin/granzyme-mediated lysis.
- T-cell activation at the immunological synapse requires three obligatory signals: Signal 1 (antigenic peptide-MHC binding TCR/CD3), Signal 2 (co-stimulation via CD28 binding CD80/CD86), and Signal 3 (polarizing cytokines including IL-2, IL-12, and IFN-gamma); Signal 1 without Signal 2 induces clonal anergy.
- Immune checkpoint pathways maintain peripheral and central tolerance: CTLA-4 acts centrally in secondary lymphoid tissues during the priming phase by outcompeting CD28 for B7 ligands, whereas PD-1 acts peripherally in the tumor microenvironment by engaging PD-L1/PD-L2 and recruiting SHP-2 phosphatase to dephosphorylate TCR signaling intermediates.
- Next-generation coinhibitory checkpoints including LAG-3 (binds MHC Class II), TIM-3 (binds galectin-9/PtdSer), and TIGIT (binds CD155/PVR) mediate non-redundant mechanisms of T-cell exhaustion that can be targeted in combination with PD-1 inhibitors (e.g., nivolumab + relatlimab).
- Tumor immune evasion operates through cellular suppression (Tregs, MDSCs, M2 TAMs), metabolic deprivation (IDO catabolizing tryptophan to kynurenine; CD39/CD73 generating immunosuppressive adenosine), and loss of antigenicity (beta-2-microglobulin loss, HLA down-regulation, JAK1/2 inactivating mutations).
Last updated: August 2026
2.3 Tumor Immunology, Antigen Presentation & Mechanisms of Immune Evasion
Immunotherapy has revolutionized modern clinical oncology, transforming prognosis across multiple advanced solid and hematologic malignancies. The success of immune checkpoint inhibitors, bispecific antibodies, and cellular therapeutics relies on an intricate understanding of anti-tumor immunity, the three-signal paradigm of T-cell activation, immune checkpoint physiology, and the active mechanisms employed by tumors to evade immune destruction.
1. The Cancer-Immunity Cycle
As conceptualized by Daniel Chen and Ira Mellman, the generation of an effective, self-sustaining anti-tumor immune response is organized as a cyclical, step-wise biological cascade. Disruption or blockade at any single step halts the cycle, resulting in tumor immune escape.
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| THE CANCER-IMMUNITY CYCLE (7 STEPS) |
| |
| [ STEP 1: RELEASE OF CANCER ANTIGENS ] |
| (Immunogenic cell death releases neoantigens, DAMPs, calreticulin) |
| | |
| v |
| [ STEP 2: CANCER ANTIGEN PRESENTATION ] |
| (Dendritic cells / APCs capture antigens, process via MHC-I & MHC-II) |
| | |
| v |
| [ STEP 3: PRIMING & ACTIVATION IN LYMPH NODES ] |
| (Signal 1: TCR-MHC | Signal 2: CD28-CD80/86 | Signal 3: IL-12/IFN-g) |
| * CTLA-4 checkpoint operates HERE (Target: Ipilimumab) |
| | |
| v |
| [ STEP 4: TRAFFICKING OF CYTOTOXIC T CELLS (CTLs) TO TUMOR ] |
| (Adhesion molecules: Selectins, Integrins, ICAM-1, VCAM-1; Chemokines) |
| | |
| v |
| [ STEP 5: INFILTRATION OF CTLs INTO TUMOR BED ] |
| (Extravasation across tumor endothelium into tumor parenchyma) |
| * Blocked in "Immune-Excluded" tumors by dense stroma & VEGF |
| | |
| v |
| [ STEP 6: RECOGNITION OF CANCER CELLS BY CTLs ] |
| (TCR specifically engages cognate peptide-MHC Class I complex) |
| * Blocked by loss of beta-2-microglobulin (B2M) or HLA downregulation |
| | |
| v |
| [ STEP 7: DESTRUCTION OF TARGET CANCER CELLS ] |
| (Perforin/Granzyme B exocytosis, FASL/FAS death receptor ligation) |
| * PD-1 / PD-L1 checkpoint operates HERE in peripheral tissue |
| (Targets: Pembrolizumab, Nivolumab, Atezolizumab, Durvalumab) |
| | |
| v (Killed tumor cells release more antigens)|
| ========================> [ RE-START CYCLE ] |
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2. Antigen Presentation & The Three-Signal T-Cell Activation Paradigm
Efficient activation of naive CD8+ cytotoxic T lymphocytes (CTLs) and CD4+ helper T cells by professional Antigen-Presenting Cells (APCs)—primarily conventional dendritic cells (cDCs)—requires three coordinated signals delivered at the immunological synapse.
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| THE THREE-SIGNAL T-CELL ACTIVATION PARADIGM |
| |
| ANTIGEN-PRESENTING CELL (APC / Dendritic Cell) |
| +-------------------------------------------------------+ |
| | [MHC-I / MHC-II] [CD80 / CD86] [IL-12, IL-2] | |
| +-------------------------------------------------------+ |
| | | | |
| | SIGNAL 1 | SIGNAL 2 | SIGNAL 3 |
| | (Antigen Specific) | (Co-stimulation)| (Polarization) |
| v v v |
| +-------------------------------------------------------+ |
| | [TCR / CD3] [CD28] [Cytokine Rec.]| |
| +-------------------------------------------------------+ |
| T LYMPHOCYTE |
| |
| * CRITICAL PHENOMENON: |
| - SIGNAL 1 + SIGNAL 2 + SIGNAL 3 ===> FULL T-CELL ACTIVATION, |
| CLONAL EXPANSION & EFFECTOR FATE |
| - SIGNAL 1 ALONE (No Signal 2) ===> T-CELL ANERGY / TOLERANCE |
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Major Histocompatibility Complex (MHC) Architecture
| Feature | MHC Class I | MHC Class II |
|---|---|---|
| Cellular Expression | All nucleated somatic cells and platelets. | Professional APCs exclusively (Dendritic cells, Macrophages, B lymphocytes). |
| Polypeptide Chains | Polymorphic alpha heavy chain (alpha1, alpha2, alpha3) non-covalently linked to invariant beta-2-microglobulin (B2M). | Polymorphic alpha chain (alpha1, alpha2) and polymorphic beta chain (beta1, beta2). |
| Peptide Source | Endogenous intracellular proteins (cytosolic proteins, viral antigens, mutated neoantigens degraded by the 20S/26S immunoproteasome). | Exogenous extracellular antigens (endocytosed, phagocytosed proteins degraded in endolysosomes). |
| Peptide Length | 8 to 10 amino acids (closed binding groove). | 13 to 25 amino acids (open binding groove). |
| Responding T-Cell Subset | CD8+ Cytotoxic T Lymphocytes (CTLs). | CD4+ Helper T Lymphocytes (Th1, Th2, Th17, Treg). |
| Primary Genes (HLA) | HLA-A, HLA-B, HLA-C. | HLA-DP, HLA-DQ, HLA-DR. |
| Cross-Presentation Exception | Specialized CD141+ / cDC1 dendritic cells can internalize exogenous tumor antigens, route them into the cytosol, and load them onto MHC Class I to prime naive CD8+ T cells. | Standard endosomal MHC-II loading pathway. |
The Three Activation Signals
- Signal 1 (Antigen Specificity): The T-cell Receptor (TCR)-CD3 complex binds the antigenic peptide embedded within the MHC molecule. The CD4 or CD8 coreceptor binds invariant regions of MHC, recruiting the tyrosine kinase Lck to phosphorylate Immunoreceptor Tyrosine-based Activation Motifs (ITAMs) on CD3-zeta chains, initiating downstream ZAP70 phosphorylation.
- Signal 2 (Co-Stimulation vs. Co-Inhibition): The canonical co-stimulatory receptor CD28 on the T cell engages B7-1 (CD80) or B7-2 (CD86) on the APC. This triggers PI3K/Akt and NF-kappaB signaling, stabilizing IL2 mRNA, driving massive cell division, and upregulating anti-apoptotic BCL-XL. If a T cell receives Signal 1 without Signal 2 co-stimulation, it enters an irreversible non-responsive state known as clonal anergy or undergoes apoptotic deletion.
- Signal 3 (Cytokine Polarization): Cytokines secreted by APCs and the microenvironment determine T-cell differentiation fate: IL-12 and IFN-gamma promote Th1 differentiation and robust CD8+ CTL cytotoxic function; IL-4 drives Th2; TGF-beta + IL-6 drives Th17; TGF-beta alone drives regulatory T cell (iTreg) conversion.
3. Immune Checkpoint Physiology & Targeted Checkpoint Blockade
Immune checkpoints are physiological inhibitory signaling pathways evolutionarily designed to prevent excessive autoimmunity and terminate inflammatory responses following pathogen clearance. Tumors co-opt these inhibitory pathways to enforce profound immune tolerance and escape destruction.
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| CTLA-4 VS. PD-1/PD-L1 IMMUNE CHECKPOINT PATHWAYS |
| |
| [ CTLA-4 AXIS: CENTRAL PRIMING PHASE ] [ PD-1 AXIS: PERIPHERAL EFFECTOR ]|
| - Location: Secondary Lymphoid Organs - Location: Tumor Microenvironment|
| (Lymph Nodes, Spleen) - Primary Target: Exhausted CTLs |
| - Primary Target: Naive / Memory T Cells - Ligands: PD-L1 (CD274), PD-L2 |
| - Ligands: CD80 (B7-1), CD86 (B7-2) |
| |
| MECHANISM OF CTLA-4: MECHANISM OF PD-1: |
| - CTLA-4 has much higher affinity - TCR engagement induces IFN-g, |
| for CD80/86 than CD28 which upregulates PD-L1 on tumor|
| - Outcompetes CD28 & strips B7 from - PD-1 binds PD-L1/PD-L2 |
| APC via trans-endocytosis - Recruits SHP-2 phosphatase to |
| - Halts broad T-cell priming ITSM motif |
| - Dephosphorylates ZAP70, CD28 & |
| THERAPEUTIC INHIBITORS: PI3K/Akt signaling cascades |
| * Ipilimumab (Anti-CTLA-4 mAb) - Inhibits cytokine release & |
| * Tremelimumab (Anti-CTLA-4 mAb) induces T-cell exhaustion |
| |
| THERAPEUTIC INHIBITORS: |
| * Anti-PD-1: Pembrolizumab, |
| Nivolumab, Cemiplimab, Dostarlimab|
| * Anti-PD-L1: Atezolizumab, |
| Durvalumab, Avelumab |
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Comprehensive Immune Checkpoint Comparison Matrix
| Checkpoint Molecule | Family & Structure | Primary Cellular Expression | Physiological Ligands & Tissue Distribution | Primary Anatomical Site of Action | Intracellular Signaling Mechanism | FDA-Approved Checkpoint Inhibitors |
|---|---|---|---|---|---|---|
| CTLA-4 (CD152) | CD28 immunoglobulin superfamily. | Activated CD4+ and CD8+ T cells; constitutively expressed on Tregs. | CD80 (B7-1) and CD86 (B7-2) on professional APCs (Dendritic cells, B cells, macrophages). | Secondary Lymphoid Tissues (Lymph nodes during initial priming). | Outcompetes CD28 for B7 binding; physically removes B7 ligands via trans-endocytosis; recruits PP2A/SHP-2 phosphatases to dampen TCR signaling. | Ipilimumab, Tremelimumab. |
| PD-1 (CD279) | CD28 superfamily coinhibitory receptor. | Activated CD8+ and CD4+ T cells, NK cells, B cells, tumor-infiltrating lymphocytes (TILs). | PD-L1 (B7-H1, CD274) on tumor cells, APCs, stromal cells.<br>PD-L2 (B7-DC, CD273) on APCs. | Peripheral Tissues & Tumor Microenvironment (Effector phase). | Recruits SHP-2 tyrosine phosphatase to immunoreceptor tyrosine-based switch motif (ITSM), dephosphorylating ZAP70 and PI3K/Akt. | Anti-PD-1: Pembrolizumab, Nivolumab, Cemiplimab, Dostarlimab.<br>Anti-PD-L1: Atezolizumab, Durvalumab, Avelumab. |
| LAG-3 (CD223) | Ig superfamily transmembrane protein. | Chronically stimulated/exhausted CD8+ and CD4+ T cells, Tregs, NK cells. | MHC Class II (binds with higher affinity than CD4), Galectin-3, FGL1. | Tumor microenvironment & draining lymph nodes. | Delivers inhibitory signals via unique cytoplasmic KIEELE motif, suppressing T-cell receptor signaling and cell cycle progression. | Relatlimab (in fixed-dose combination with Nivolumab: Opdualag). |
| TIM-3 (HAVCR2) | T-cell immunoglobulin and mucin domain. | Th1 cells, CD8+ CTLs, dendritic cells, macrophages, NK cells. | Galectin-9, Phosphatidylserine (PtdSer), HMGB1, CEACAM1. | Peripheral tumor microenvironment. | Phosphorylation of conserved tyrosine residues releases Bat3, recruiting Src family kinases that inhibit TCR and NF-kappaB signaling. | Investigational combinations (Cobolimab, Sabatolimab). |
| TIGIT | Ig superfamily receptor with ITIM domain. | CD8+ T cells, NK cells, memory T cells, Tregs. | CD155 (PVR) and CD112 (Nectin-2) on tumor cells and APCs. | Peripheral tumor bed. | Competes with co-stimulatory receptor CD226 for CD155 binding; transmits inhibitory signals via cytoplasmic ITIM/ITT motifs. | Investigational combinations (Tiragolumab, Domvanalimab). |
4. The Immunosuppressive Tumor Microenvironment (TME)
Beyond expressing surface checkpoint ligands, tumors establish multi-component cellular and biochemical defenses that paralyze infiltrating cytotoxic lymphocytes.
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| IMMUNOSUPPRESSIVE CELLULAR & METABOLIC NETWORKS IN THE TME |
| |
| +---------------------------------------------------------------------+ |
| | IMMUNOSUPPRESSIVE LEUKOCYTES | |
| | | |
| | 1. REGULATORY T CELLS (Tregs: CD4+ CD25+ FOXP3+) | |
| | - Secrete immunosuppressive TGF-beta, IL-10, and IL-35. | |
| | - Express high CD25 (IL-2R alpha) to act as "IL-2 sponges". | |
| | - Express high CTLA-4 to strip CD80/86 from APCs. | |
| | | |
| | 2. MYELOID-DERIVED SUPPRESSOR CELLS (MDSCs) | |
| | - Express Arginase-1 (Arg-1): Depletes L-arginine (stops TCR). | |
| | - Express iNOS: Produces Nitric Oxide & ROS (nitrylates TCR). | |
| | | |
| | 3. TUMOR-ASSOCIATED MACROPHAGES (M2-Polarized TAMs) | |
| | - Stimulated by IL-4/IL-13/IL-10; secrete VEGF, TGF-beta, MMP-9.| |
| +---------------------------------------------------------------------+ |
| | |
| v |
| +---------------------------------------------------------------------+ |
| | METABOLIC IMMUNE SUPPRESSION | |
| | | |
| | 1. INDOLEAMINE 2,3-DIOXYGENASE (IDO-1 / IDO-2) | |
| | - Converts L-Tryptophan ===> Kynurenine | |
| | - Tryptophan depletion halts T-cell proliferation via GCN2. | |
| | - Kynurenine binds AhR, driving naive CD4+ conversion to Tregs. | |
| | | |
| | 2. ADENOSINERGIC ECTONUCLEOTIDASE PATHWAY (CD39 / CD73) | |
| | - Extracellular ATP ===[CD39]===> AMP ===[CD73]===> Adenosine | |
| | - Adenosine binds A2A Receptors (A2AR) on CTLs and NK cells | |
| | - Increases intracellular cAMP, paralyzing cytotoxicity. | |
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5. Tumor Immunophenotypes & Mechanisms of Immune Escape
Solid tumors exhibit distinct immune microenvironment architectures that predict responsiveness to immune checkpoint blockade.
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| THE THREE TUMOR IMMUNE MICROENVIRONMENT PHENOTYPES |
| |
| [ INFLAMED / "HOT" ] [ IMMUNE-EXCLUDED ] [ IMMUNE-DESERT / "COLD" ]|
| +--------------------+ +--------------------+ +--------------------+|
| | T T T T | | T T T T T T T T T | | ||
| | [ TUMOR ] T | | === STROMA / CAF ==| | [ TUMOR ] ||
| | T T T T | | [ TUMOR ] | | ||
| | T T T | | === STROMA / CAF ==| | (No T-cell infil- ||
| +--------------------+ +--------------------+ +--------------------+|
| - High CD8+ TILs - T cells trapped in - Total absence of ||
| in tumor parenchyma peritumoral stroma T cells inside or ||
| - High PD-L1 expression - Dense desmoplasia/TGF-b around tumor ||
| - High TMB / MSI-H - Defective extravasation- Low TMB / Non-immuno||
| * HIGHEST RESPONSE TO * REQUIRES STROMAL OR * REQUIRES PRIMING / ||
| ANTI-PD-(L)1 MONOTHERAPY ANTI-ANGIOGENIC COMBO CELLULAR STRATEGIES ||
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Molecular Mechanisms of Primary and Acquired Immunotherapy Resistance
- Loss of Beta-2-Microglobulin (B2M): Inactivating mutations or deletions in the B2M gene prevent the assembly and cell surface trafficking of all MHC Class I heterodimers (HLA-A, -B, -C). CD8+ cytotoxic T lymphocytes can no longer recognize tumor neoantigens regardless of PD-1 blockade, causing acquired resistance.
- Inactivation of Interferon-Gamma Receptor Signaling (JAK1 / JAK2 Mutations): When effector T cells engage tumor antigens, they secrete IFN-gamma, which normally binds IFNGR1/2 on tumor cells, triggering JAK1/JAK2 phosphorylation and STAT1/3 activation to upregulate antigen presentation machinery and PD-L1. Loss-of-function JAK1 or JAK2 mutations render tumor cells completely insensitive to IFN-gamma, preventing growth arrest and leading to immune escape.
- Loss of Target Neoantigens: Downregulation or genetic deletion of specific immunogenic target epitopes (e.g., loss of CD19 surface expression in B-ALL via alternative splicing following CD19-directed CAR-T cell therapy).
- PTEN Loss & Oncogenic Wnt/Beta-Catenin Hyperactivation: Inactivating mutations in PTEN or activating mutations in CTNNB1 (beta-catenin) suppress chemokine expression (CCL4, CXCL9/10), physically excluding dendritic cells and CD8+ T cells from entering the tumor parenchyma, establishing an immune-desert phenotype.
Test Your Knowledge
A clinical oncology specialist is explaining the physiological and pharmacologic differences between anti-CTLA-4 therapy (ipilimumab) and anti-PD-1 therapy (pembrolizumab) to a clinical pharmacy resident. Which statement correctly distinguishes their primary anatomical site of action and molecular signaling mechanism?
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Test Your Knowledge
A 59-year-old patient with unresectable, treatment-naive metastatic cutaneous melanoma initiates first-line dual checkpoint inhibitor therapy with nivolumab (anti-PD-1) plus relatlimab (anti-LAG-3) as a fixed-dose combination. What is the biological rationale and molecular mechanism of targeting LAG-3 in combination with PD-1 blockade?
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Test Your Knowledge
A 64-year-old patient with metastatic cutaneous melanoma achieves a complete radiographic response on single-agent pembrolizumab monotherapy lasting 22 months. However, routine surveillance imaging reveals new, rapidly enlarging pulmonary and adrenal metastases. Core biopsy of a progressive lung lesion demonstrates that tumor cells continue to express high PD-L1 (TPS 90%), but next-generation sequencing reveals an acquired homozygous loss-of-function frameshift mutation in the beta-2-microglobulin (B2M) gene. What is the precise molecular mechanism driving this acquired resistance to anti-PD-1 immunotherapy?
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Test Your Knowledge
In the tumor microenvironment, metabolic enzyme upregulation serves as a potent biochemical mechanism of immune suppression. Specifically, tumor cells and myeloid-derived cells frequently overexpress Indoleamine 2,3-dioxygenase-1 (IDO-1). What metabolic pathway does IDO-1 catalyze, and how does this enzymatic activity suppress effector T-cell function while promoting immune tolerance?
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