Cancer Immunology and Principles of Immunotherapy
The two arms
Innate immunity (NK cells, macrophages, dendritic cells) acts within hours without memory; adaptive immunity (T and B lymphocytes) is antigen-specific and generates memory. Antigens are presented on MHC class I to CD8 cytotoxic T cells and on MHC class II to CD4 helper T cells.
The central axis
T-cell activation needs signal 1 (TCR-MHC-peptide), signal 2 (costimulation, CD28-B7) and signal 3 (cytokines). Two brakes oppose this: CTLA-4, which competes with CD28 for CD80/86, and PD-1, which binds PD-L1/PD-L2. Checkpoint inhibitors therefore act in the lymph node during priming (anti-CTLA-4) or in the tumour microenvironment during effector phase (anti-PD-1/PD-L1).
Predictive biomarkers
Mismatch-repair deficiency and MSI-high status, tumour mutational burden, PD-L1 expression (threshold and assay dependent) and immune gene signatures. PD-L1 is an imperfect biomarker: some PD-L1-negative patients respond.
Toxicities
Immune-related adverse events include colitis, hepatitis, pneumonitis, hypophysitis, thyroiditis, rash and adrenal insufficiency. Corticosteroids are first line, with infliximab for steroid-refractory colitis; endocrine events need long-term hormone replacement. Cytokine release syndrome and neurotoxicity are the hallmark toxicities of CAR-T cells, not typical irAEs.
Response patterns
Pseudoprogression (early enlargement followed by regression) and hyperprogression must be distinguished from true progression; iRECIST was created to define unconfirmed versus confirmed progression.
Traps
Do not swap anti-CTLA-4 and anti-PD-1 mechanisms or toxicity spectra, and remember that any organ inflamed 2 to 12 weeks into checkpoint blockade is an irAE until proven otherwise.