9.Tumor Immunity & Immune Evasion

1. IMMUNE SURVEILLANCE – why cancer immunity exists

Who proposed immune surveillance?

• Paul Ehrlich – first suggested tumors arise regularly and the immune system recognizes & destroys them.
• Later expanded by Lewis Thomas + Macfarlane Burnet – immune system constantly patrols body to detect transformed (tumor) cells.

Key supporting evidence

• Tumor-specific T cells + antibodies identified in cancer patients.
• Tumors infiltrated with more cytotoxic lymphocytes (CTLs) show better prognosis.
• Cancer rates increase in immunodeficient hosts (humans + mice).
• Immunotherapy → clinical benefit via re-activating antitumor immunity.

Three big truths of tumor immunity

1. Tumors display antigens (abnormal protein flags).
2. Tumors evolve immune evasion mechanisms.
3. Removing brakes restores T-cell attack (checkpoint therapy).

2. TUMOR ANTIGENS — what the immune system sees

Tumor cells express abnormal/signature proteins: "flags" that immune system can detect.

A. Neoantigens = mutation-derived peptides

• From driver and passenger mutations.
• Mutagens:

– UV → skin cancers

– Tobacco carcinogens → lung cancers

• Present novel peptides → immune system recognizes them as foreign.

B. Unmutated tumor-associated antigens

Normal proteins aberrantly expressed:

• Overexpressed differentiation antigens:

– Tyrosinase overexpressed in melanomas.

• Cancer-testis antigens (e.g., MAGE, NY-ESO-1):

– Normally expressed in testis, which lacks MHC-I → immune system never tolerized.

– When tumor expresses them + MHC I → T cells can respond.

C. Viral tumor antigens

Viruses insert foreign genes → viral proteins expressed in tumor:

• HPV → cervical + oropharyngeal cancers
• EBV → B-cell lymphomas (especially immunosuppressed)
• CD8+ T cells can attack virus-bearing tumor cells
• In HIV/AIDS, weakened immune system → ↑ viral tumor incidence

3. EFFECTIVE ANTI-TUMOR IMMUNITY – how the immune system fights cancer

A. Alarm signals — DAMPs

• Rapid tumor growth → hypoxia, necrosis
• Necrotic death releases Danger-Associated Molecular Patterns (DAMPs)
• Activate dendritic cells + macrophages.

B. Cross-presentation

• DCs eat tumor debris → migrate to draining LN
• Present peptides on MHC-I to naive CD8 T cells
• This pathway = essential for tumor-specific CTL priming.

C. CD8+ T cells (CTLs) — major killers

• Activated in LN → proliferate → circulate to tumor → recognize antigen–MHC I → kill tumor cells.

D. CD4+ Th1 helpers

• Produce IFN-γ → enhances:

– macrophage killing

– MHC expression

– CTL responses

E. Proof CTLs matter

• Tumors escape by losing MHC-I (β2-microglobulin mutations).
• Tumors with more CTL + Th1 infiltration → better prognosis.

F. Other contributing immune cells

• NK cells (target MHC-I–negative cells)
• macrophages (either M1 antitumor or M2 protumor)
• dendritic cells

4. IMMUNE EVASION — how tumors resist immune attack

A. Immunoediting

Immune system eliminates susceptible tumor clones → selects resistant variants → clinically detectable cancer emerges.

B. Escape methods

i) Antigen presentation defects

• Mutate β2-microglobulin → MHC-I cannot assemble → T cells cannot recognize tumor.

ii) T-cell inhibitory pathways

• Tumor expresses PD-L1 → binds PD-1 on T cells → exhaustion.
• CTLA-4 on T cells inhibits activation (competes with CD28 for B7 ligands).

C. Checkpoint blockade therapy

• Antibodies block PD-1/PD-L1 or CTLA-4 → remove brakes → restore CTL activity.
• Clinical benefit in:

– melanoma

– NSCLC

– bladder cancer

– Hodgkin lymphoma

• Solid tumors response rate ~10–30% (higher in hematologic malignancies).

D. Toxicities of checkpoint therapies

Because brakes also suppress autoimmunity:

• autoimmune-like inflammation
• colitis
• systemic inflammatory syndromes

→ treated with immunosuppressive drugs.

E. CAR-T cell therapy

• Patient T cells modified with Chimeric Antigen Receptor (CAR)
• Receptor = antibody-derived extracellular domain + intracellular activation signals
• Excellent responses in B-ALL
• Risk: cytokine storm; limited success outside blood cancers; still evolving.

F. Tumor-driven immune reprogramming

Tumors modify surroundings to aid growth:

• recruit Th2 cells
• polarize macrophages → M2
• secrete immunosuppressive mediators
• ↑ angiogenesis + fibrosis

G. Challenges + future direction

• Responses unpredictable.
• Need biomarkers for immune strength + tumor evasion pathway.
• Combination therapies + sequencing strategies being investigated.
• Goal: broad, durable responses with fewer toxicities.

5. GENOMIC INSTABILITY – why tumors accumulate mutations

A. Mutation sources vs cancer rarity

• Mutagens continuously damage DNA.
• Cell DNA repair systems prevent malignant transformation.

B. Defective repair = ↑ cancer risk

Inherited/acquired DNA repair defects → elevated mutation burden.

KEY DNA repair syndromes

1. Mismatch repair — HNPCC (Lynch syndrome)

• Genes repair mismatched bases.
• Two-hit model: inherit 1 mutated allele → acquire 2nd hit.
• Causes:

– colorectal cancers (right colon especially)

– microsatellite instability (hallmark)

• MSI appears in:

– all HNPCC cancers

– ~15% sporadic Colorectal carcinoma

2. Nucleotide excision repair — XP

• Fixes UV-induced pyrimidine crosslinks.
• Absent repair → extremely high skin cancer risk.

3. Homologous recombination repair defects

• Disorders:

– Bloom syndrome

– Ataxia-telangiectasia

– Fanconi anemia

• Shared features:

– autosomal recessive

– hypersensitivity to radiation/cross-linking drugs

– neurologic defects (AT), anemia (Fanconi), developmental delay (Bloom)

• ATM senses radiation → activates p53 for repair/apoptosis.

4. BRCA1 & BRCA2

• Together → ~50% familial breast cancers
• BRCA1 risks:

– breast

– ovarian epithelial cancer (women)

– prostate (men)

• BRCA2 risks:

– breast (men + women)

– ovarian

– prostate

– pancreas

– bile duct

– stomach

– melanoma

– B-cell cancers

• Both require loss of both alleles for tumor to develop.
• Rare in sporadic breast cancers (unlike TP53 + APC).

5. Regulated genomic instability in lymphoid cells

Normal immune diversification intentionally breaks DNA:

• RAG1/2 → V(D)J recombination
• AID → class switching + somatic hypermutation

→ errors can → lymphoid cancers.

🧠 EXAM REFLEX BLOCK — Tumor Immunity & Genomic Instability (ZERO-OMISSION)

Use this as a rapid recall + examiner-trap lock.

🔐 IMMUNE SURVEILLANCE — CORE REFLEX

• Immune surveillance concept proposed by Paul Ehrlich, expanded by Macfarlane Burnet and Lewis Thomas
• Tumors arise frequently → immune system normally eliminates them
• Evidence:
• Tumor-specific CD8⁺ T cells + antibodies detectable
• High CTL infiltration = better prognosis
• Immunodeficiency → ↑ cancer
• Checkpoint inhibitors work → proves immunity exists

👉 Exam line:

Cancer exists despite immune surveillance, not because it is absent.

🏷️ TUMOR ANTIGENS — WHAT T CELLS SEE

1️⃣ Neoantigens (MOST immunogenic)

• Derived from mutations (driver + passenger)
• UV → melanoma; smoking → lung cancer
• Foreign peptides on MHC-I

2️⃣ Tumor-associated self antigens

• Overexpressed differentiation antigens (e.g. tyrosinase in melanoma)
• Cancer-testis antigens (MAGE, NY-ESO-1)
• Normally in testis (no MHC-I)
• When expressed with MHC-I → immune recognition

3️⃣ Viral antigens

• HPV → cervical, oropharyngeal cancer
• EBV → B-cell lymphomas
• Immunosuppression → ↑ viral cancers

👉 Exam trap:

Tumor antigens are not always mutated.

⚔️ EFFECTIVE ANTI-TUMOR IMMUNITY — SEQUENCE

1. Tumor necrosis → DAMPs
2. Dendritic cell activation
3. Cross-presentation
• Tumor antigen on MHC-I
• Primes naïve CD8⁺ T cells in LN
4. CD8⁺ CTLs
• Recognize antigen–MHC-I
• Kill via perforin/granzyme
5. CD4⁺ Th1
• IFN-γ → ↑ MHC, ↑ macrophage killing, ↑ CTLs
6. NK cells
• Kill MHC-I–negative tumors

👉 Proof CTLs matter:

Loss of β2-microglobulin → ↓ MHC-I → immune escape

🧬 IMMUNE EVASION — HOW CANCER ESCAPES

Immunoediting (3 phases)

• Elimination → Equilibrium → Escape

Escape mechanisms

• Antigen loss
• β2-microglobulin mutation → no MHC-I
• Checkpoint activation
• PD-L1 (tumor) → PD-1 (T cell) → exhaustion
• CTLA-4 blocks CD28–B7 costimulation

🧪 CHECKPOINT THERAPY — EXAM MUST-KNOW

• Anti-PD-1 / PD-L1 / CTLA-4 antibodies
• Remove inhibitory brakes → restore CTLs
• Cancers:
• Melanoma
• NSCLC
• Bladder
• Hodgkin lymphoma
• Response rate:
• Solid tumors: 10–30%
• Hematologic: higher

Toxicity

• Autoimmune-type:
• Colitis
• Dermatitis
• Endocrinopathies
• Treat with immunosuppression

🧬 CAR-T THERAPY — REFLEX

• Autologous T cells engineered with CAR(chymeric antigen receptor)
• Antibody-like antigen recognition (MHC-independent)
• Excellent in B-ALL
• Risks:
• Cytokine release syndrome
• Limited success in solid tumors

🧠 TUMOR MICROENVIRONMENT — IMMUNE REPROGRAMMING

• ↑ Th2 cells
• Macrophage shift → M2
• Immunosuppressive cytokines
• Angiogenesis + fibrosis
• Net effect → immune paralysis

🧬 GENOMIC INSTABILITY — WHY MUTATIONS ACCUMULATE

• DNA damage is constant
• Cancer is rare → repair systems normally protect
• Repair defects = cancer predisposition

🧠 DNA REPAIR SYNDROMES — HIGH-YIELD TABLE IN WORDS

🔹 Mismatch Repair — HNPCC (Lynch)

• MSI present
• Right-sided colon cancer
• All HNPCC + ~15% sporadic CRC

🔹 Nucleotide Excision Repair — Xeroderma Pigmentosum

• UV damage unrepaired
• Massive skin cancer risk

🔹 Homologous Recombination Defects

• Bloom, Fanconi, Ataxia-telangiectasia
• Radiation sensitivity
• ATM → p53 activation

🔹 BRCA1 / BRCA2

• Require biallelic loss
• BRCA1: breast, ovarian (epithelial), prostate
• BRCA2: breast (♂♀), ovary, prostate, pancreas, bile duct, stomach, melanoma, B-cell cancers
• Rare in sporadic breast cancer

🔹 Physiologic genomic instability (lymphocytes)

• RAG1/2 → V(D)J recombination
• AID → class switch + somatic hypermutation
• Errors → lymphoid malignancy

🧠 FINAL EXAM SUPER-LOCK (ONE-LINE)

Cancer survives by balancing mutation-generated antigenicity with immune evasion, enabled by genomic instability and reversible T-cell suppression.