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.
Base Tumor-Immune PhysiCell Model
AGENT_BASED
C++/XML/CSV
PhysiCell
Grammar-based PhysiCell agent-based model of a heterogeneous tumor under immune surveillance. Immune cells chemotax toward tumor-derived signals, form physical contacts, and attempt contact-mediated killing, making this a useful executable baseline for the anti-tumor T cell response segment of this module.
Official sample model from the manuscript-synced grammar_samples release. Most relevant to the "Anti-Tumor T Cell Response" and early immune-escape portions of this module.
Extended Tumor-Immune PhysiCell Model
AGENT_BASED
C++/XML/CSV
PhysiCell
Expanded grammar-based PhysiCell tumor-immune model with a richer set of immune-tumor interaction rules than the base example. This is a better executable analogue for adaptive immune resistance and state-dependent suppression within checkpoint-responsive tumors.
Official sample model from the manuscript-synced grammar_samples release. Best treated as a reusable executable reference for checkpoint-sensitive tumor-immune interaction logic rather than a disease-specific digital twin.
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.
Downstream
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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.
Used by disorders
Thymoma
as PD-L1 Mediated Adaptive Immune Resistance
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.