Immune escape mechanisms in cancer

Name the 10 immune escape mechanisms

Mechanism	What it means
1. Insufficient tumor-specific T-cell frequency	Too few T cells recognise the tumor.
2. Insufficient T-cell avidity	T cells recognise tumor antigen too weakly to respond effectively.
3. T-cell tolerisation	T cells become unresponsive to tumor antigens.
4. Treg suppression	Regulatory T cells inhibit anti-tumor effector cells.
5. Reduced T-cell function and tumor apoptosis resistance	T cells kill poorly, or tumor cells resist death.
6. Lack of tumor homing and infiltration	T cells cannot reach or enter the tumor.
7. Tumor antigen or HLA downregulation	Tumor cells become harder for T cells to recognise.
8. Tumor apoptosis resistance	Tumor cells survive even after immune recognition.
9. Tumor-derived immunosuppressive factors	Tumors release signals that inhibit immunity.
10. DC suppression/depletion and M2/MDSC accumulation	Antigen presentation weakens and suppressive myeloid cells accumulate.

What is intratumoral heterogeneity

Different regions of the same tumor may have different antigen expression, immune-cell densities, stromal barriers and suppressive signals.

Two mechanisms of tumor-cell PD-L1 expression

• Innate or constitutive expression: oncogenic signalling and other tumor-intrinsic mechanisms drive PD-L1 expression.

• Adaptive immune resistance: immune-derived signals, particularly IFN-γ, induce PD-L1 expression in response to an ongoing immune attack.

PD-L1 expression can be evidence of an existing immune response as well as a mechanism of immune escape. explain

T-cell activation → IFN-γ production → increased PD-L1 → PD-1 signalling → reduced T-cell activity.

How is TGF related to TME

TGF-β can contribute to an immunosuppressive TME by supporting Treg responses.

How does tumor cells becoming less visible to cytotoxic T cells. How does Nk cells play into this

tumor loses HLA class I expression, CD8+ T cells may no longer recognise it effectively, even if they are present and functional. More susceptible to NK cells when HLA is low - missing self recognition

Phenotype of HLA loss

Causes of HLA class I loss. Which one is restorable

HARD MHC-I lesions: genetic alterations leading to permanent loss. IRREVERSIBLE

SOFT MHC-I lesions: Reversible suppression of HLA class I expression. For example, impaired interferon signalling can reduce HLA expression. IFNγ stimulation RESTORES IT

Name some factors in the TME that has suppressive anti tumour immunity

• Tregs.

• Th2 cells.

• Suppressive cytokines.

• M2-like macrophages.

• Monocytic MDSCs.

• Granulocytic MDSCs.

You use checkpoint inhibitor for a patient but the tumour is not supressed. why

Resistance to immunotherapy can be multifactorial. Blocking one pathway may not overcome a TME that suppresses immunity through several mechanisms. Such as

• DC function and antigen presentation.

• T-cell priming and activation.

• Effector T-cell function.

• Immune-cell trafficking.

• Susceptibility of tumor cells to killing.

Tumor-conditioned tissues frustrate DC maturation. Explain

• Mature, immunogenic DCs: support effective T-cell responses and can contribute to anti-tumor immunity.

• Immature, tolerogenic DCs: may fail to activate effector T cells and can support immune tolerance

Functional state of DCs depends on the balance of signals they receive.

IL-10, IL-6 and PGE₂ - tumor-associated suppressive side,

IFN-α and IL-12 - supporting immune activation.

Name 3 therapeutic targeting pathway for immune activation

• COX-2 inhibitors (COX2i) - reduce PGE₂ production.

• STAT3 inhibitors (STAT3i)- Interfere with signalling that supports tumor-associated immunosuppression

• p38 MAPK inhibitors (p38 MAPKi) - targets another signalling pathway involved in inflammatory and myeloid-cell regulation.

Therapeutic interference with Wnt signalling in cases of cervical adenoca

Wnt pathway interference → improved cDC1 presence or function → improved T-cell priming and infiltration → a more favourable environment for PD-1 blockade.

What therapy you will do for this

PD1 CHECKPOINT BLOCKADE

what therapy

CAR T CELL THERAPY

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