This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "immune_checkpoint_blockade#Adaptive Immune Resistance"). The module defines the expected pathophysiology structure; conforming nodes in disorder files should include the corresponding cell types, biological processes, and causal edges, specialized to their tumor context. Key tumor-specific substitutions: MSI-H CRC uses dMMR-driven hypermutation as the neoantigen source; melanoma uses UV-induced mutation burden; virus-associated cancers (NPC, EBV gastric) use viral antigen presentation alongside somatic neoantigens.
Neoantigen Generation
trigger
Tumor cells accumulate somatic mutations, some of which produce novel peptides (neoantigens) presented on MHC class I molecules. The neoantigen source varies by tumor type: mismatch repair deficiency in MSI-H cancers, UV-induced mutations in melanoma, viral antigens in virus-associated cancers, or high tumor mutational burden from other causes. Higher neoantigen load generally correlates with greater immunogenicity and checkpoint inhibitor responsiveness.
Downstream
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Anti-Tumor T Cell Response
Anti-Tumor T Cell Response
effector
Dendritic cells present tumor neoantigens to naive T cells, priming CD8+ cytotoxic T lymphocytes that infiltrate the tumor and recognize tumor cells via MHC-I/neoantigen complexes. CTLA-4 acts as a brake at this priming stage in lymph nodes, competing with CD28 for B7 ligand binding. The magnitude of the T cell response depends on neoantigen immunogenicity, dendritic cell function, and the balance of co-stimulatory versus co-inhibitory signals during priming.
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Adaptive Immune Resistance
The anti-tumor immune response itself triggers adaptive upregulation of checkpoint ligands by tumor cells, creating a negative feedback loop.
Adaptive Immune Resistance
central effector
Tumor cells upregulate PD-L1 (and PD-L2) expression in response to interferon-gamma secreted by infiltrating T cells. This adaptive mechanism represents a co-opted physiological immune homeostasis pathway: PD-L1 engagement of PD-1 on effector T cells delivers inhibitory signals that suppress cytotoxicity, cytokine production, and proliferation. Tumors with active adaptive immune resistance are termed "immune-adapted" and are the best candidates for PD-1/PD-L1 blockade therapy, as the underlying anti-tumor immunity exists but is being actively suppressed.
Downstream
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T Cell Exhaustion and Immune Escape
Chronic checkpoint engagement drives T cells toward an exhausted phenotype with progressive loss of effector function.
T Cell Exhaustion and Immune Escape
consequence
Persistent antigen exposure combined with chronic PD-1 signaling drives tumor-infiltrating T cells toward an exhausted phenotype characterized by progressive loss of cytokine production, cytotoxicity, and proliferative capacity, with upregulation of multiple inhibitory receptors (PD-1, LAG-3, TIM-3, TIGIT). The immunosuppressive tumor microenvironment is further reinforced by recruitment of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. This results in functional immune escape despite physical T cell presence in the tumor.