Orris

Tumor antigens, immune surveillance and immune checkpoint inhibitors (pd1 pdl1) in cancer Robbins based md pathology exams 10 marks question

Reading File
Finding Sources
Finding Sources
Searching PubMed

cancer immune checkpoint inhibitors

Searching the Web

NCI immune checkpoint inhibitors PD-1 PD-L1 cancer

Reading File
Reading File
Finding Sources
Finding Sources
Reading File
Reading File
Reading File

Tumor Antigens, Immune Surveillance and PD-1/PD-L1 Checkpoint Inhibitors

Introduction

Immune surveillance is the ability of the immune system to continuously recognize and eliminate newly arising malignant cells. Tumor cells express antigens that can be recognized as non-self, chiefly by CD8+ cytotoxic T lymphocytes (CTLs). Tumors that ultimately grow have escaped or suppressed this immune response. Robbins, Cotran & Kumar Pathologic Basis of Disease, pp. 293-296.

1. Tumor antigens

Tumor antigens are molecules expressed on cancer cells that evoke an immune response. Protein antigens presented with MHC class I are recognized by CD8+ CTLs, the most important cells in protective antitumor immunity.

Types

TypeSourceExamples / importance
NeoantigensMutations in driver genes and passenger genes produce altered proteins not previously encountered by the immune systemMore common in tumors with high mutation burden, such as UV-induced melanoma and smoking-associated cancers. Higher mutation load often predicts better response to checkpoint blockade.
Overexpressed or aberrantly expressed self proteinsNormal proteins expressed in excess or in an abnormal tissue contextTyrosinase in melanoma.
Cancer-testis antigensGenes usually silent in adult tissues but expressed in tumor cells and testicular germ cellsMAGE family. Testicular germ cells lack MHC I expression, so these proteins are functionally tumor-specific for CTL recognition.
Viral tumor antigensProteins encoded by oncogenic viruses in virus-associated cancersHPV antigens in cervical carcinoma; EBV antigens in some lymphomas and nasopharyngeal carcinoma.
Key point: Only mutant peptides that bind the individual's HLA/MHC molecules and are displayed to T cells act as effective neoantigens. Robbins, Cotran & Kumar Pathologic Basis of Disease, pp. 293-294.

2. Immune surveillance and antitumor immune response

The immune system scans tissues for transformed cells and destroys them before clinically evident cancer develops.

Evidence for immune surveillance

  1. Tumor-specific T cells and antibodies can be demonstrated in patients with cancer.
  2. Dense intratumoral T-cell infiltration is often associated with a better prognosis.
  3. Immunodeficient individuals have increased risk of cancers, particularly virus-associated cancers, such as EBV-related lymphomas and HPV-associated cancers.
  4. Regression of cancers with checkpoint inhibitors supports the presence of pre-existing but suppressed antitumor immunity.
Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 293.

Main effector mechanisms

A. CD8+ cytotoxic T cells - principal mechanism
  • Tumor proteins are processed and presented as peptides on MHC class I molecules.
  • Dendritic cells take up tumor antigens, migrate to draining lymph nodes, and activate tumor-specific T cells.
  • Activated CD8+ CTLs kill tumor cells through perforin-granzyme and Fas-FasL pathways.
B. CD4+ helper T cells
  • Produce cytokines, especially IFN-gamma.
  • Enhance CTL activation and stimulate macrophage-mediated tumor killing.
C. NK cells
  • Kill tumor cells with reduced or absent MHC class I expression, the so-called “missing-self” recognition.
  • Can also mediate antibody-dependent cellular cytotoxicity.
D. Macrophages
  • Activated by IFN-gamma and may kill tumor cells through reactive oxygen species, nitric oxide, and lysosomal enzymes.

3. Tumor immune evasion

Although tumors may be antigenic, established cancers escape immune destruction by several mechanisms:
  1. Loss of tumor antigen expression
    • Antigen-negative variants survive selection by the immune system.
  2. Decreased MHC class I expression
    • Often due to defects involving beta-2 microglobulin.
    • Tumor antigens cannot be presented to CD8+ CTLs.
  3. Expression of inhibitory checkpoint ligands
    • Tumors express PD-L1 and PD-L2, inhibiting effector T cells through PD-1.
  4. Immunosuppressive tumor microenvironment
    • Tumor secretion of TGF-beta, IL-10, prostaglandins and other suppressive mediators.
    • Recruitment of regulatory T cells and myeloid-derived suppressor cells.
  5. T-cell exhaustion and poor T-cell infiltration
    • “Hot” tumors have T-cell infiltration and are more likely to respond to checkpoint blockade.
    • “Cold” tumors lack effective immune-cell infiltration and respond poorly.
Robbins, Cotran & Kumar Pathologic Basis of Disease, pp. 295-296.

4. PD-1/PD-L1 immune checkpoint pathway

Normal role

The PD-1/PD-L1 pathway is a normal inhibitory mechanism that prevents excessive immune reactions and autoimmunity.
  • PD-1 (programmed cell death protein-1): inhibitory receptor on activated T cells, especially chronically stimulated/exhausted T cells.
  • PD-L1 (programmed death-ligand 1): expressed on tumor cells, antigen-presenting cells, and some normal cells.
  • PD-1 also binds PD-L2.

In cancer

Tumor cells may overexpress PD-L1 or PD-L2. Binding of PD-L1 on the tumor cell to PD-1 on the CTL sends an inhibitory signal that suppresses T-cell activation, cytokine secretion, proliferation, and cytotoxic tumor killing.
Tumor antigen on MHC I  →  TCR on CD8+ T cell → activation and killing

But:
PD-L1 on tumor cell  ─────→  PD-1 on T cell
                              ↓
                        inhibitory signal
                              ↓
                     T-cell exhaustion / no killing
PD-1 engagement activates intracellular phosphatases that inhibit T-cell activation signaling. Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 295.

5. PD-1/PD-L1 checkpoint inhibitors

These are monoclonal antibodies that block the inhibitory PD-1-PD-L1 interaction and restore the capacity of T cells to kill cancer cells.
Anti-PD-1 or anti-PD-L1 antibody
          ↓
Blocks PD-1 - PD-L1 interaction
          ↓
Removes inhibitory “brake” on CTLs
          ↓
Restored T-cell-mediated tumor cell killing

Important drugs

TargetDrugs
Anti-PD-1Pembrolizumab, nivolumab, cemiplimab
Anti-PD-L1Atezolizumab, durvalumab, avelumab

Uses

Checkpoint inhibitors are used in several advanced malignancies, including:
  • Melanoma
  • Non-small-cell lung carcinoma
  • Renal cell carcinoma
  • Urothelial carcinoma
  • Hodgkin lymphoma
  • Hepatocellular carcinoma
  • Head and neck squamous cell carcinoma
  • Some mismatch-repair-deficient or microsatellite-instability-high tumors
They tend to be more effective in tumors with:
  • High tumor mutational burden
  • Many neoantigens
  • PD-L1 expression in appropriate clinical settings
  • Pre-existing intratumoral T-cell infiltration
Robbins, Cotran & Kumar Pathologic Basis of Disease, pp. 293, 295-296. The NCI checkpoint inhibitor overview similarly describes PD-1/PD-L1 blockade as releasing the inhibitory signal that prevents T-cell tumor killing.

Adverse effects

By removing normal inhibitory control of immunity, checkpoint inhibitors can cause immune-related adverse events, resembling autoimmune disease:
  • Dermatitis
  • Colitis
  • Hepatitis
  • Pneumonitis
  • Thyroiditis and other endocrinopathies
  • Nephritis

Conclusion

Tumor antigens, particularly mutation-derived neoantigens, initiate predominantly CD8+ T-cell-mediated antitumor immunity. Immune surveillance eliminates many nascent tumors, but clinically evident cancers evade immunity through antigen/MHC loss and immunosuppressive mechanisms, especially PD-L1 expression. Anti-PD-1 and anti-PD-L1 antibodies block this inhibitory checkpoint, reactivate exhausted T cells, and have become major therapies for several cancers.
Exam-ending line: Immune checkpoint blockade is based on removing tumor-induced inhibitory “brakes” on T cells, thereby restoring host antitumor immunity.
This is a shared conversation. Sign in to Orris to start your own chat.