Mechanisms of Immune Evasion by Cancers

Slide 1 · Mechanisms of Immune Evasion by Cancers

Tumor recognition • inhibitory pathways • suppressive microenvironment

Antigen display

Immune checkpoints

Tumor microenvironment

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Trace the normal CD8+ cytotoxic T-cell response to tumor antigens.

Distinguish antigen-presentation failure, checkpoint inhibition, and microenvironmental suppression.

Explain the rationale, response patterns, and adverse effects of checkpoint blockade.

Slide 3 · Immune evasion enables growth in competent hosts

Many malignant tumors arise without an overt systemic immunodeficiency.

A growing tumor can avoid recognition or resist antitumor effector mechanisms.

Evasion mechanisms are multiple and are not mutually exclusive.

Potential T-cell response

Tumor-acquired escape

Continued tumor growth

Slide 4 · Effective surveillance requires a complete recognition chain

Tumor antigen

MHC I display

CTL activation

Tumor killing

Antigen production, MHC class I display, T-cell priming, and effector activity are all required.

Disruption at any stage may permit a tumor clone to survive.

Slide 5 · Recognizable tumor antigens have several origins

Mutated proteins

Aberrant cellular proteins

Viral proteins

Mutated driver or passenger gene products can create neoantigens.

Overexpressed or aberrantly expressed proteins can become targets.

Oncogenic viral proteins provide foreign antigens in some cancers.

Slide 6 · Dendritic cells link tumor death to adaptive immunity

Tumor cell death

Antigen uptake

Dendritic migration

Lymph node

Dendritic cells ingest tumor material released during tumor cell death.

They migrate to draining lymph nodes and present antigens to T cells.

Slide 7 · CD8+ T cells require antigen recognition and costimulation

Antigen-specific signal

Costimulatory signal

Signal 1: T-cell receptor recognition of peptide–MHC class I.

Costimulatory molecules on antigen-presenting cells support activation.

Tumor-derived danger signals may promote APC costimulatory function.

Slide 8 · Activated CTLs travel back to the tumor

Node priming

CTL migration

Tumor recognition

Cell killing

Primed tumor-specific CTLs leave lymph nodes and enter tumor tissue.

Antigen recognition at the tumor permits direct cytotoxic killing.

Slide 9 · CD8+ CTLs are the dominant antitumor effectors

Most relevant tumor antigens are displayed by class I MHC molecules.

CTLs can directly and serially kill antigen-bearing tumor cells.

Evasion may interrupt either recognition or effector-cell activity.

Peptide–MHC I

Specific CD8+ CTL

Target-cell death

Slide 10 · NK activity highlights a limitation of MHC loss

CD8+ CTL / needs peptide–MHC I

NK cell / may kill MHC I-low target

Loss of MHC I impairs conventional CD8+ CTL recognition.

Activated NK cells can kill some MHC I-low tumor targets without prior sensitization.

The importance of NK cells against spontaneous human tumors remains less firmly established.

Slide 11 · Five complementary routes to immune escape

Antigen or MHC loss

Checkpoint engagement

Soluble inhibitors

Tregs and MDSCs

Suppressive stroma

Antigen loss and defective class I presentation prevent recognition.

Inhibitory receptors restrain activation of tumor-reactive T cells.

Soluble mediators, regulatory cells, and suppressive stroma limit immunity.

Slide 12 · Antigen-loss variants become invisible to specific CTLs

Target expressed

Antigen-loss clone

Failed specific recognition

A CTL targeting one tumor epitope cannot recognize a clone lacking that antigen.

Loss of the target does not imply that the entire tumor lacks other antigens.

Slide 13 · Escape can occur through failure to produce the antigen

Antigen retained

Antigen absent

Antigen-positive cells remain candidates for cognate T-cell attack.

Antigen-negative variants cannot engage CTLs specific for that missing epitope.

The explanatory figure distinguishes antigen loss from MHC loss.

Slide 14 · MHC class I makes cytosolic tumor antigens visible

Intracellular protein

Peptide–MHC I

T-cell receptor

CTL response

Endogenously synthesized tumor proteins furnish peptides for MHC class I display.

Peptide–MHC I complexes can be recognized by antigen-specific CD8+ CTLs.

Slide 15 · Reduced HLA class I expression blocks CD8+ recognition

Some tumor cells express abnormally low HLA class I levels.

Failure of cytosolic antigen display allows escape from CTLs even if antigens remain.

Reduced staining or expression is mechanistically different from absence of antigen.

Tumor antigen present

HLA I display reduced

CTL recognition reduced

Slide 16 · β2-microglobulin is essential for stable HLA class I

β2M alteration

HLA class I deficiency

Reduced CD8+ recognition

β2-microglobulin is the invariant subunit of the HLA class I heterodimer.

Mutation or silencing of its gene is a prominent mechanism of reduced HLA I expression.

The result is deficient display of tumor peptides to conventional CTLs.

Slide 17 · Antigen-processing defects can mimic MHC loss

The textbook immune-evasion figure includes altered genes required for antigen processing.

A tumor may possess antigenic proteins yet fail to present the relevant peptide.

Separate the antigen source from the class I presentation apparatus.

Tumor protein

Processing or MHC defect

Insufficient surface display

Slide 18 · MHC escape creates a CTL–NK distinction

Property

CD8+ CTL

NK cell

Principal recognition

Peptide–MHC I

Can react to selected MHC I-low targets

Need for priming

Antigen-specific activation

May act without prior sensitization

Source caveat

Major antitumor effector

Spontaneous-tumor role less established

Slide 19 · Recognition failure is not identical to T-cell paralysis

Target not visible

T cell inhibited despite target

Recognition failure: Absent antigen or defective peptide–MHC display.

Functional inhibition: Tumor-reactive T cells exist but are suppressed.

The mechanism matters when reasoning about checkpoint treatment.

Slide 20 · Analyze immune escape at four checkpoints

Antigen?

MHC display?

T-cell function?

Tissue entry?

A conceptual diagnostic sequence asks whether antigen, presentation, priming, and effector access are intact.

The stages identify possible failure points; They are not a validated clinical testing algorithm.

Slide 21 · Immune checkpoints physiologically restrain responses

Inhibitory receptor systems help maintain self-tolerance.

Tumors can exploit these brakes to reduce antitumor T-cell activity.

Therapeutic blockade can restore function at the cost of inflammatory toxicity.

Inhibitory signal

Weaker T-cell function

Tumor advantage

Slide 22 · T-cell activation depends on two distinct signals

TCR + peptide–MHC

CD28 + B7

TCR recognition of peptide–MHC alone does not guarantee full activation.

CD28 costimulation via B7 molecules on APCs promotes priming.

Inhibitory checkpoints can counter these activating interactions.

Slide 23 · CTLA-4 inhibits the priming phase of T-cell responses

B7 on APC

CTLA-4 engagement

Less CD28 costimulation

CTLA-4 is an inhibitory receptor on T cells.

Its engagement with B7 limits use of B7 by activating CD28.

The source places this regulatory interaction at antigen-presenting cells.

Slide 24 · B7 competition explains the CTLA-4 brake

B7 → CD28: Activation

B7 → CTLA-4: Inhibition

With CD28 engagement, APC B7 molecules support T-cell activation.

When CTLA-4 engages B7, effective costimulation is reduced.

Both receptor pathways influence the same priming interaction.

Slide 25 · Inadequate costimulation can cause unresponsiveness

Reduced B7–CD28 engagement may prevent sensitization to tumor antigen.

Inhibitory signaling may also favor prolonged T-cell unresponsiveness.

A priming defect may precede an effective tumor-specific CTL response.

Weak costimulation

Incomplete priming

Persisting tumor

Slide 26 · Anti–CTLA-4 releases a brake on T-cell priming

CTLA-4 blocked

B7–CD28 available

CTL activation

Blocking CTLA-4 permits greater access of CD28 to B7 on APCs.

The resulting costimulation can promote tumor-specific T-cell activation.

This acts on a different inhibitory step from PD-1 blockade.

Slide 27 · PD-1 suppresses responses of effector T cells

PD-L1 or PD-L2

PD-1 on T cell

Inhibitory signaling

PD-1 is an inhibitory receptor on tumor-reactive effector T cells.

Ligand binding suppresses signaling needed for T-cell activation and function.

Slide 28 · PD-1 signaling recruits a cellular phosphatase

Engagement of PD-1 activates inhibitory phosphatase-mediated signaling.

T-cell activation falls despite recognition of a tumor antigen.

This represents functional suppression rather than loss of antigen display.

PD-1 ligation

Phosphatase activated

T-cell response inhibited

Slide 29 · PD-L1 and PD-L2 serve as inhibitory ligands

Ligand on tumor cell

PD-1 on effector T cell

Tumor cells may upregulate PD-L1 and PD-L2 on their surface.

Either ligand can engage the PD-1 receptor on T cells.

Upregulation provides an active means of suppressing effector responses.

Slide 30 · Checkpoint-ligand genes can be genomically altered

The source describes amplification or translocation affecting PD-L1 or PD-L2 genes.

Such alterations can drive excessive inhibitory-ligand expression.

Do not assume that all tumors with PD-L1 expression share the same genomic mechanism.

Gene amplification or translocation

Ligand overexpression

PD-1 inhibition

Slide 31 · Blocking PD-1 or its ligand can restore CTL function

PD-1 axis blocked

CTL signal restored

Tumor cell killing

Antibodies against PD-1 or PD-L1 interrupt inhibitory receptor engagement.

Relief of PD-1 signaling can re-enable tumor-specific T-cell activity.

The source illustrates restored CTL killing after checkpoint blockade.

Slide 32 · CTLA-4 and PD-1 constrain different phases

Feature

CTLA-4

PD-1

Dominant teaching site

APC–T-cell priming

Effector response in tumor tissue

Core interaction

CTLA-4 with B7

PD-1 with PD-L1/PD-L2

Effect of blockade

Restores costimulation

Removes inhibitory effector signal

Slide 33 · Checkpoint blockade acts on host immunity

Direct cytotoxic agent

Checkpoint inhibitor

Checkpoint antibodies do not themselves replace tumor-specific antigen recognition.

They remove inhibitory signaling imposed on existing or newly primed immune responses.

A tumor lacking necessary immune targets may remain resistant.

Slide 34 · Immunosuppressive secretions form a second escape axis

TGF-β

IL-10

PGE₂

Tryptophan metabolites

VEGF

Tumors can release molecules that restrain immune responses.

TGF-β, IL-10, PGE₂, tryptophan-derived metabolites, and VEGF.

Some specific mechanisms are established; Others are presented as suspected.

Slide 35 · TGF-β is a potent tumor-associated immunosuppressant

Many tumors secrete TGF-β in substantial amounts.

TGF-β suppresses host immune responses and may promote tumor persistence.

The source identifies this as a comparatively well-supported soluble mechanism.

Tumor secretion

TGF-β exposure

Immune suppression

Slide 36 · IL-10 is a candidate soluble suppressive mediator

IL-10 is listed among factors produced by tumors that may inhibit immunity.

Several such mediators with varying degrees of certainty.

Do not infer a defined contribution for every tumor type from this general list.

Tumor-associated IL-10

Possible host-response inhibition

Context-dependent effect

Slide 37 · Prostaglandin E₂ is implicated in immune suppression

Prostaglandin E₂ is identified among soluble products suspected of inhibitory activity.

Its presence illustrates that immune evasion is not restricted to protein checkpoints.

The supplied section does not provide a tumor-specific quantitative effect.

Tumor-associated mediator

PGE₂

Potential immune inhibition

Slide 38 · Tryptophan metabolites provide a metabolic route

Tumor metabolism

Tryptophan derivatives

Immune restraint

Certain tryptophan-derived metabolites are implicated in suppression of host immunity.

The text does not attribute the effect to a specific enzyme or quantitative threshold.

Conceptually, metabolic products may inhibit immunity without loss of antigen.

Slide 39 · VEGF may impair T-cell entry into the tumor bed

Circulating T cell

VEGF-associated barrier

Reduced tumor entry

The supplied chapter notes that VEGF can inhibit migration of T cells from vessels into tumors.

Thus antigen-specific CTLs may be present systemically yet poorly represented within tumor tissue.

This is an access problem, not necessarily a priming problem.

Slide 40 · Soluble factors target different stages of immunity

Factor / group

Source-described connection

Interpretive caution

TGF-β

Potent immunosuppression

Magnitude varies by tumor

IL-10, PGE₂, metabolites

Suspected host-response inhibition

Mechanisms not specified in excerpt

VEGF

May impede T-cell movement into tumor

Immune exclusion is multifactorial

Slide 41 · Some tumors recruit regulatory T cells

Tumor-derived signals

More Tregs

Reduced antitumor response

Tumor products may favor development of immunosuppressive regulatory T cells (Tregs).

Tregs can contribute to suppression of antitumor T-cell responses.

The source uses cautious language: “some studies suggest” this mechanism.

Slide 42 · Myeloid-derived suppressor cells appear in the escape model

The caption to Figure 7.40 includes myeloid-derived suppressor cells (MDSCs).

Such cells are represented as producing factors that suppress T-cell function.

The extracted text does not define MDSC subsets or subtype-specific mechanisms.

MDSC in tumor bed

Suppressive factors

Diminished T-cell function

Slide 43 · Stromal and innate cells can reinforce tumor escape

Tumors frequently contain innate immune populations and nonmalignant stromal cells.

These cells can participate in local suppression of host responses.

Some underlying mechanisms remain undefined.

Stromal + innate cells

Local suppressive ecology

Immune dysfunction

Slide 44 · The microenvironment integrates cellular and soluble brakes

Inhibitory ligands

Soluble suppressors

Treg / MDSC

Stromal cells

Suppressive ligands may act at the tumor–T-cell interface.

Secreted factors can act beyond direct cell contact.

Tregs, MDSCs, and stroma may amplify a hostile immune environment.

Slide 45 · Immune exclusion differs from dysfunctional infiltration

Limited T-cell entry

T cells present but restrained

Excluded or “cold” tumors have few associated immune effector cells.

Inflamed tumors contain T cells but may still suppress their function.

Checkpoint blockade presumes a biologically restorable antitumor response.

Slide 46 · Immune evasion is a layered, nonexclusive process

Recognition barrier

Checkpoint inhibition

Suppressive tissue niche

One tumor may lose antigen display and express inhibitory ligands.

Regulatory cells and soluble mediators can simultaneously reinforce suppression.

No single mechanism should be presumed to explain every resistant tumor.

Slide 47 · Hot and cold describe the tumor immune context

Hot: T-cell infiltrated

Cold: Immune-cell poor

“Hot” tumors exhibit histologic evidence of a host T-cell response.

“Cold” tumors lack substantial associated immune-cell infiltrates.

These broad descriptors summarize tissue context, not a standalone validated diagnostic assay.

Slide 48 · Intra-tumoral T cells correlate with favorable response

The source notes that T-cell infiltrates often correlate with better prognosis.

Immune-infiltrated tumors are more likely to respond to checkpoint blockade.

Association does not mean that every infiltrated tumor will respond.

T-cell infiltrates

Existing antitumor response

Higher likelihood of response

Slide 49 · Cold tumors may resist checkpoint blockade

Few T cells

Checkpoint blocked

Limited effect possible

In immune-cell-poor tumors there may be little antitumor T-cell activity to reactivate.

Gliomas are offered as an example of a relatively cold and poorly responsive setting.

Strategies to convert cold tumors into hot tumors are under investigation.

Slide 50 · Neoantigen burden is a treatment-response correlate

More mutations

More candidate neoantigens

Greater immune visibility

More somatic mutations can produce additional non-self peptide targets.

Tumor neoantigen burden correlates with the effectiveness of immunomodulatory therapy.

The association is not an individual-patient response guarantee.

Slide 51 · Mismatch repair deficiency is a mechanistic exemplar

MMR deficiency

Mutation accumulation

Neoantigens

Checkpoint sensitivity

Defective mismatch repair permits accumulation of DNA replication errors.

These tumors frequently carry particularly high mutation burdens.

This biology to increased sensitivity to PD-1–axis blockade.

Slide 52 · High mutational burden is predictive, not sufficient

High neoantigens + intact immunity

High neoantigens + escape mechanism

Neoantigens help only if they are generated, presented, and recognized.

MHC I loss or profound immune exclusion may undermine checkpoint response.

Multiple escape mechanisms can coexist in a highly mutated tumor.

Slide 53 · Clinical sensitivity varies widely between cancers

Textbook examples

Relative responsiveness

Interpretation

Melanoma; Hodgkin lymphoma; NSCLC

Often responsive

Responses remain heterogeneous

Glioma; pancreatic cancer

Generally poorly responsive

Other escape routes may dominate

Any histology

Response not assured

Mechanism and tissue context matter

Slide 54 · Histologic immune context is biologically informative

T-cell infiltrates are evidence of a host response to tumor tissue.

Their distribution and abundance may inform why checkpoint therapy could work.

The supplied excerpt does not define a numeric T-cell threshold or scoring system.

Tumor section

Visible lymphocyte infiltrate

Immune context interpretation

Slide 55 · Checkpoint resistance can occur at multiple levels

Antigen absent

MHC I reduced

Cold tumor

Other suppressors

Antigen-negative or MHC-deficient cells evade recognition.

Poor T-cell entry leaves few effectors in tumor tissue.

Suppressive cells or soluble factors may act despite checkpoint inhibition.

Slide 56 · Checkpoint blockade benefits only a subset of tumors

Clinical responses differ markedly across histologic tumor types.

Tumors that rely less on CTLA-4 or PD-1 inhibition may fail to respond.

Restoring one checkpoint pathway need not reverse all immune-escape mechanisms.

Checkpoint target blocked

Other escape persists

Incomplete response

Slide 57 · Durable remissions may involve immune memory

CTL reactivation

Tumor control

Possible memory T cells

Checkpoint blockade can produce prolonged tumor control in some patients.

The source proposes development of tumor-specific memory T cells as a possible explanation.

This mechanism is plausible but is presented as an interpretation, not proven for every responder.

Slide 58 · Distinct checkpoints provide a combination rationale

CTLA-4 / priming

PD-1 / effector

CTLA-4 regulates the balance of costimulation during priming.

PD-1 acts on inhibitory signaling in effector responses.

Targeting both may address separable immune suppressive stages.

Slide 59 · Combined CTLA-4 and PD-1 blockade is source-supported

The source describes combined checkpoint blockade as more effective than anti–CTLA-4 alone in selected settings.

Melanoma and lung cancer are its examples.

This is a mechanistic teaching point, not a claim of universal treatment superiority.

Priming restraint relieved

Effector brake relieved

Potential added activity

Slide 60 · Checkpoint toxicities follow directly from their biology

Self-tolerance brake removed

Immune activation

Organ inflammation

Physiologic inhibitory checkpoints limit excessive immune activation.

Their blockade can weaken peripheral tolerance to self antigens.

The resulting adverse effects include inflammatory or autoimmune tissue injury.

Slide 61 · Immune-related injury can affect several organs

Colon

Lungs

Endocrine organs

Heart

Skin

Colon, lungs, endocrine organs, heart, and skin.

The involved organ determines clinical surveillance and intervention.

Severe toxicity may necessitate stopping otherwise effective treatment.

Slide 62 · Application: A tumor loses β2-microglobulin

CLINICAL–MECHANISTIC PROBLEM

Scenario: Tumor cells retain mutated proteins but show loss of functional HLA class I display.

Question: Which immune effector is most directly disadvantaged?

Mechanistic answer: Antigen-specific CD8+ CTLs cannot efficiently recognize tumor peptide–MHC I.

Slide 63 · Application: An MMR-deficient cancer

CLINICAL–MECHANISTIC PROBLEM

Scenario: A tumor accumulates many mutations due to mismatch-repair deficiency.

Question: Why could PD-1 blockade be effective?

Mechanistic answer: Mutation-derived neoantigens may provide targets for restored T-cell responses.

Slide 64 · Application: An immune-cell-poor tumor

CLINICAL–MECHANISTIC PROBLEM

Scenario: A tumor biopsy shows few infiltrating T cells despite expression of an inhibitory ligand.

Question: Why may checkpoint blockade alone underperform?

Mechanistic answer: Too few active tumor-reactive T cells may be present to release from inhibition.

Slide 65 · Choose the mechanism from the observed failure

Observed failure

Mechanistic category

Immediate consequence

Absent tumor epitope

Antigen-loss escape

Specific CTL cannot recognize

Reduced HLA class I

Presentation escape

Peptide display to CTL impaired

PD-L1 engagement of PD-1

Checkpoint suppression

Effector T-cell activation inhibited

Few intratumoral T cells

Poor immune access / cold state

Little local response to restore

Slide 66 · The organizing model: Visibility, activation, access

Antigen visibility

T-cell activation

Tumor-bed access

Visibility: Tumor antigens must be displayed by a functional presentation pathway.

Activation: Inhibitory receptors and regulatory signals must not dominate.

Access: Tumor-reactive T cells must reach and function within tumor tissue.

Slide 67 · Key concepts

Recognition

Loss of tumor antigens or class I MHC prevents cognate CTL recognition.

Regulation

CTLA-4 and PD-1 pathways inhibit different stages of T-cell responses.

Microenvironment

Suppressive secretions, Tregs, myeloid cells, and stroma reinforce immune escape.

Treatment

Checkpoint response depends on antigenic potential and immune context; Toxicity reflects loss of immune restraint.

Slide 68 · Questions to consolidate the mechanisms

Why might an HLA class I-deficient tumor resist checkpoint therapy despite retaining many mutations?

Why can CTLA-4 and PD-1 blockade be mechanistically complementary?

Why are inflammatory and autoimmune adverse effects predictable consequences of checkpoint inhibition?