Tumor Immunology & Immunotherapy Mechanisms
How tumors hide from T cells, and how drugs take the brakes off
Immune surveillance and immunoediting
Surveillance. Immunity destroys many transformed cells before a tumor forms. The clearest evidence: transplant recipients and people with advanced HIV develop far more cutaneous squamous cell carcinoma and virus-driven cancers (Kaposi sarcoma, EBV lymphoma, HPV-related anogenital cancer).
- EliminationNK cells, CD8 T cells and IFN-γ destroy most newly transformed cells.
- EquilibriumSurvivors stay dormant, sometimes for years, while immune pressure selects less immunogenic variants.
- EscapeEdited clones that hide from or suppress immunity grow into clinical cancer.
Tumor antigens and antitumor effectors
| Class | Examples | Significance |
|---|---|---|
| Neoantigens (somatic mutations) | Mutant KRAS or TP53 peptides; frameshift peptides in MSI-high tumors | Truly tumor specific; never seen in thymic selection |
| Oncoviral proteins | HPV E6/E7; EBV latent proteins | Wholly foreign |
| Cancer-testis antigens | MAGE, NY-ESO-1 (melanoma and others) | Normally limited to germ cells, which lack MHC I |
| Overexpressed or lineage self-proteins | HER2, tyrosinase, CD19, CD20, prostatic acid phosphatase | Tolerance weakens T-cell responses; ideal antibody and CAR targets |
Mutational burden. Each nonsynonymous mutation can yield a neoantigen, so high tumor mutational burden (TMB) makes a tumor visible to T cells: UV-driven melanoma, smoking-related NSCLC and mismatch-repair-deficient (dMMR), microsatellite-instability-high (MSI-high) tumors. dMMR stems from germline MLH1, MSH2, MSH6 or PMS2 mutations (Lynch syndrome) or sporadic MLH1 promoter hypermethylation, mostly in colorectal and endometrial cancer, and shows as lost MMR protein staining.
Pembrolizumab received the first tissue-agnostic approval: any MSI-high/dMMR solid tumor, whatever its organ of origin.
Effectors. CD8 cytotoxic T cells recognize tumor peptide on MHC I and kill with perforin/granzyme and Fas ligand. NK cells need no priming: inhibitory KIRs sense self MHC I, so a cell lacking MHC I is killed (missing self), and NKG2D detects stress ligands such as MICA/MICB; NK cells also perform ADCC through CD16. IFN-γ from both raises MHC I expression and activates macrophages.
How tumors escape
- Hiding antigen. Loss of MHC I, β2-microglobulin (required for MHC I surface expression) or TAP, and JAK1/JAK2 mutations that make cells deaf to IFN-γ hide peptides from CD8 cells and cause primary or acquired resistance to PD-1 blockade.
- Inhibitory ligands. Tumor and myeloid cells up-regulate PD-L1, often induced by IFN-γ from attacking T cells (adaptive resistance). Hodgkin lymphoma amplifies the PD-L1/PD-L2 locus on 9p24.1 and responds well to PD-1 blockade.
- Suppressor cells. FOXP3+ CD25+ Tregs consume IL-2 and express CTLA-4; myeloid-derived suppressor cells and M2 macrophages deplete arginine and release reactive oxygen species.
- Soluble factors and exhaustion. TGF-β and IL-10 blunt effector T cells and dendritic cells; chronic antigen exposure leaves exhausted, PD-1-high T cells.
Checkpoint inhibitors and their toxicity
CTLA-4. On activated T cells and Tregs, CTLA-4 binds B7 (CD80/CD86) on APCs with higher affinity than CD28, switching off costimulation during priming in lymph nodes. Ipilimumab blocks it and broadens activation of new tumor-reactive clones.
PD-1/PD-L1. PD-1 on chronically stimulated T cells binds PD-L1/PD-L2 on tumor and stromal cells and damps TCR signaling in tissue. Blocking either partner re-arms exhausted effectors in the tumor (melanoma, NSCLC, renal cell, urothelial and head and neck cancer, Hodgkin lymphoma). Ipilimumab plus nivolumab adds efficacy and toxicity.
| Feature | Anti-CTLA-4 | Anti-PD-1 / anti-PD-L1 |
|---|---|---|
| Drugs | Ipilimumab | Nivolumab, pembrolizumab, cemiplimab (PD-1); atezolizumab, durvalumab, avelumab (PD-L1) |
| Site and phase | Lymph node; priming | Tumor and peripheral tissue; effector phase |
| Toxicity | More frequent and severe; colitis, hypophysitis | Less frequent; thyroiditis, pneumonitis relatively common |
Abatacept and belatacept are the mirror image: CTLA-4-Ig fusion proteins that occupy B7 to suppress T cells in rheumatoid arthritis and transplantation.
Immune-related adverse events. Unleashed self-reactive T cells attack almost any organ, usually weeks to months into therapy: dermatitis, colitis, hepatitis, pneumonitis, thyroiditis, hypophysitis, adrenalitis and insulin-deficient diabetes often presenting as DKA. After excluding infection (C. difficile for diarrhea), moderate or severe events → hold the drug and give systemic glucocorticoids; steroid-refractory colitis → infliximab, refractory hepatitis → mycophenolate. Endocrine irAEs are usually permanent and need hormone replacement (levothyroxine, hydrocortisone, insulin).
Checkpoint myocarditis is rare but often fatal, especially with combined CTLA-4 and PD-1 blockade; stop the drug and give high-dose steroids promptly.
Engineered T cells, BCG and vaccines
CAR T cells. Autologous T cells are virally transduced with a chimeric antigen receptor: an antibody-derived scFv fused to CD3ζ plus a CD28 or 4-1BB costimulatory domain. The scFv binds intact surface antigen, so recognition is MHC independent. Anti-CD19 products treat B-ALL and large B-cell lymphoma; anti-BCMA products treat multiple myeloma.
Bispecific T-cell engagers. Blinatumomab tethers CD19 on B-ALL blasts to CD3 on any T cell, forming a cytolytic synapse without MHC.
CRS and ICANS. Mass T-cell activation releases IL-6, IFN-γ and IL-1 from T cells and macrophages: fever, hypotension and hypoxia with very high ferritin and CRP. Tocilizumab (anti-IL-6 receptor) is first line, adding glucocorticoids for severe cases; siltuximab binds IL-6 itself. ICANS (confusion, aphasia, seizures, cerebral edema) is treated with glucocorticoids, because tocilizumab does little for isolated ICANS.
Intravesical BCG. Live attenuated Mycobacterium bovis instilled into the bladder provokes local innate and Th1 inflammation that clears non-muscle-invasive urothelial carcinoma and carcinoma in situ; risks are BCG cystitis and disseminated BCG infection.
Sipuleucel-T. The patient's own APCs are loaded ex vivo with a prostatic acid phosphatase–GM-CSF fusion protein and reinfused, modestly prolonging survival in metastatic castration-resistant prostate cancer. PSA is a marker, not the target.