The hallmarks of cancer immune evasion

Review: The Hallmarks of Cancer Immune Evasion

DOI: 10.1016/j.ccell.2024.09.010

Claudia Galassi, Timothy A. Chan, Ilio Vitale & Lorenzo Galluzzi

Central Idea: This review proposes a "Three Cs" framework (Camouflage, Coercion, and Cytoprotection) to categorize the diverse mechanisms cancer cells utilize to evade the immune system.

Key Concepts:

• Camouflage: Hiding from immune detection.
  • Downregulation of MHC class I molecules and/or associated proteins (e.g., B2M, TAP1/2).
  • Epigenetic silencing of MHC and antigen processing genes.
  • Impaired chemoattraction through altered ATP, ANXA1, and chemokine (e.g., CXCL10, CCL2) signaling.
  • Defective ICD-driven phagocytosis via altered CALR exposure or signaling.
  • Physical immune exclusion by CAFs, TAMs, or TANs via mechanisms including TGFβ1 signaling or NET formation.
• Coercion: Suppressing immune cell activity.
  • Upregulation of immune checkpoint ligands (e.g., PD-L1, HLA-E, CD47).
  • Defective PRR, DAMP, and type I IFN signaling (e.g., altered CGAS-STING pathway, viral mimicry impairment).
  • Altered cytokine secretion favoring anti-inflammatory molecules (e.g., CCL2, TGFβ1, CXCL8, IL33) over pro-inflammatory factors (e.g., IFNs, IL1B).
  • Metabolic modulation of the TME by depleting nutrients (e.g., glucose, glutamine, methionine) or releasing immunosuppressive metabolites (e.g., adenosine, kynurenine, lactate, TCA cycle byproducts, bioactive lipids like PGE2).
• Cytoprotection: Resisting immune-mediated killing.
  • Altered immunological synapse formation.
  • Defective cell death signaling (e.g., mutations in CASP8, downregulation of FAS, impaired TNF/IFNG signaling).
  • Compensatory mechanisms like autophagy upregulation.

Clinical Translation:

• The review highlights existing and emerging immunotherapies targeting the "Three Cs."
• Approved agents: ICIs targeting PD-1/PD-L1, CTLA-4, LAG-3; CAR T cells; bispecific antibodies; some cytokine therapies.
• Investigational strategies: Inhibitors of other immune checkpoints (e.g., TIM-3, TIGIT, VISTA, NKG2A, CD47); metabolic modulators targeting glutamine, methionine, lactate, or adenosine pathways; STING agonists; and agents targeting multiple mechanisms simultaneously (e.g., epigenetic modifiers, PRMT5/KDM1A inhibitors).

Limitations & Future Directions:

• Some evasion mechanisms don't neatly fall into the "Three Cs" framework.
• Intratumoral heterogeneity: Different tumor regions might employ different "Cs."
• Need for more specific and effective therapies targeting metabolic pathways.
• Importance of developing biomarkers to predict response to specific immunotherapies, especially those beyond PD-L1 expression.
• The need for better understanding the hierarchy of the three "C"s as drivers of resistance and thus targets for therapy.