Immune Checkpoint-Responsive Cancers (Adaptive Immune Resistance)

name: Immune Checkpoint-Responsive Cancers
display_name: Immune Checkpoint-Responsive Cancers (Adaptive Immune Resistance)
creation_date: "2026-06-13T00:00:00Z"
description: >-
  A group of malignancies that share the adaptive-immune-resistance mechanism
  exploited by immune checkpoint blockade. Tumor neoantigens elicit an
  anti-tumor T cell response; in response the tumor microenvironment upregulates
  inhibitory checkpoints (notably PD-L1) that drive T cell exhaustion and immune
  escape. Because this resistance is the therapeutic target, these tumors are
  clinically responsive to PD-1/PD-L1 (and CTLA-4) checkpoint inhibitors. The
  group is defined by a shared treatment-response mechanism rather than by tissue
  of origin, and accordingly spans diverse anatomic sites and histologies.
grouping_basis:
- SHARED_MECHANISM
- SHARED_TREATMENT_RESPONSE
grouping_rationale: >-
  Grouped on a shared tumor-immune mechanism and its therapeutic corollary: each
  member conforms to the immune_checkpoint_blockade module (neoantigen ->
  anti-tumor T cell response -> adaptive immune resistance / PD-L1 upregulation
  -> T cell exhaustion) and is treated with checkpoint inhibitors. Members are
  kept as separate Disease entries because the source of immunogenicity differs
  (high tumor mutational burden, mismatch-repair deficiency, viral antigens, or
  9p24.1/PD-L1 amplification) and the tissue contexts and companion driver
  alterations are distinct. The criteria are NECESSARY (each listed member shows
  checkpoint-responsive adaptive immune resistance); the listed members are a
  representative curated set. (Because the criteria are NECESSARY, the evaluator
  audits only the listed members; it does not auto-discover the other
  module-conforming tumors as candidates — that would require SUFFICIENT or
  NECESSARY_AND_SUFFICIENT criteria.)
membership_criteria:
- description: >-
    A member conforms to the immune-checkpoint-blockade module's adaptive immune
    resistance node — tumor PD-L1 upregulation driving T cell exhaustion that is
    reversible with checkpoint inhibition.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: CONFORMS_TO_MODULE
    module: immune_checkpoint_blockade#Adaptive Immune Resistance
    description: >-
      Conforms to the adaptive immune resistance node of the immune checkpoint
      blockade module.
members:
- member: BRAF V600 Mutant Melanoma
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      High UV-induced tumor mutational burden generates abundant neoantigens;
      melanoma was the index checkpoint-inhibitor-responsive tumor. The BRAF
      V600 driver additionally allows targeted therapy, giving an immunotherapy/
      targeted-therapy interplay.
    gene:
      preferred_term: BRAF
      term:
        id: hgnc:1097
        label: BRAF
- member: MSI-High Colorectal Cancer
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Mismatch-repair deficiency produces a hypermutated, frameshift-neoantigen-
      rich tumor that is strongly checkpoint-responsive, in contrast to
      microsatellite-stable colorectal cancer — the prototype of biomarker-
      defined (MSI/dMMR) immunotherapy response.
- member: Classic Hodgkin Lymphoma
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Recurrent 9p24.1 amplification constitutively overexpresses PD-L1/PD-L2,
      producing genetically hardwired adaptive immune resistance and exceptional
      checkpoint-inhibitor sensitivity — a copy-number (not mutational-burden)
      route to PD-L1 dependence.
    gene:
      preferred_term: JAK2
      term:
        id: hgnc:6192
        label: JAK2
- member: Bladder Urothelial Carcinoma
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Carcinogen-associated high mutational burden makes urothelial carcinoma
      checkpoint-responsive; FGFR3 alterations define a parallel targetable
      subset, distinguishing immunotherapy-responsive from FGFR-driven tumors.
    gene:
      preferred_term: FGFR3
      term:
        id: hgnc:3690
        label: FGFR3
- member: Clear Cell Renal Cell Carcinoma
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Despite modest mutational burden, ccRCC is highly immune-infiltrated and
      checkpoint-responsive, reflecting an angiogenesis/immune microenvironment
      mechanism rather than neoantigen load (VHL-pathway biology).
- member: Hepatocellular Carcinoma
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Chronic inflammatory (viral/metabolic) hepatocarcinogenesis yields an
      immunosuppressive but checkpoint-responsive tumor, typically combined with
      anti-angiogenic therapy.
- member: Endometrial Carcinoma
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The mismatch-repair-deficient / POLE-ultramutated molecular subgroups are
      strongly checkpoint-responsive; PTEN-driven tumors anchor the broader
      endometrial biology.
    gene:
      preferred_term: PTEN
      term:
        id: hgnc:9588
        label: PTEN
- member: Nasopharyngeal Carcinoma
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      EBV-driven viral antigens and PD-L1 upregulation make nasopharyngeal
      carcinoma checkpoint-responsive — the viral-antigen route to adaptive
      immune resistance (contrast the mutational-burden route).
notes: >-
  A novel SHARED_TREATMENT_RESPONSE grouping defined by a treatment-response
  mechanism rather than tissue of origin. Members are a representative curated
  subset of the many tumors conforming to the immune_checkpoint_blockade module.
  (The criteria are NECESSARY, so `just check-groupings` audits only the listed
  members; the broader set of conforming tumors is enumerated separately via the
  module's conformance list, not auto-flagged as candidates by the evaluator.)
  The differentiating axis is the source of immunogenicity: high mutational
  burden (melanoma, urothelial), mismatch-repair deficiency (MSI-H colorectal,
  endometrial), PD-L1 copy-number amplification (Hodgkin lymphoma), viral antigen
  (nasopharyngeal), or inflamed microenvironment (renal, hepatocellular).
  MONDO mapping: deliberately omitted. This is a SHARED_TREATMENT_RESPONSE
  grouping defined by a therapeutic mechanism (checkpoint-blockade-responsive
  adaptive immune resistance), not by tissue of origin or lineage; MONDO has no
  "checkpoint-responsive cancer" class and the members span many unrelated
  neoplasm branches, so no single MONDO class applies.