PD-1

OVERVIEW

Programmed death protein 1 (PD-1) is a type 1 cell surface receptor expressed by activated CD4+ and CD8+ T cells, natural killer (NK) T cells, and antigen-presenting cells (APCs).^1,2

The PD-1 receptor has two ligands, programmed death ligand-1 (PD-L1) and programmed death ligand-2 (PD-L2), which are mainly expressed on APCs. Receptor/ligand interactions maintain immune homeostasis by reducing T-cell priming and inhibiting effector T-cell proliferation and function while increasing immunosuppressive regulatory T cell (Treg) function.^1,3,4
T-cell activation by APCs via stimulation of the T-cell receptor (TCR) by major histocompatibility complexes (MHCs), costimulated by CD28 interactions with CD80 or CD86, upregulates the expression of PD-1 on those T cells.^5,6,13
- Prolonged TCR stimulation during an ongoing immune response can cause upregulated PD-1 expression.¹³
- Tumor cells can express PD-L1 (and PD-L2, not shown) as a consequence of inflammatory cytokines and/or oncogenic signaling pathways. PD-1:PD-L1 binding inhibits TCR-mediated positive signaling, leading to reduced proliferation, reduced cytokine secretion, and reduced survival; this results in a downregulation of the immune response.¹³

IMPLICATIONS IN CANCER

Appropriation of the PD-L1/PD-1 pathway can be one mechanism by which the tumor evades immunosurveillance.⁷
- Induction of PD-L1 expression on tumor cells, tumor-infiltrating APCs, and/or immune cells within the tumor microenvironment leads to suppression of immune responses and poor anti-tumor responses, permitting cancer progression and metastasis.^8,9
- Immunohistochemistry (IHC) has also detected PD-L1 expression in infiltrating lymphocytes in a variety of tumors.¹⁰
Effective cancer immunotherapy depends on the status of the immune response in the tumor microenvironment. Patients with tumors that contain a high density of tumor-infiltrating lymphocytes (TILs) are most likely to respond to immunotherapy; however, this is not sufficient for complete cancer eradication.
Evidence of T-cell exhaustion has been observed in T cells infiltrating many solid tumors.¹¹
- Chronic exposure to tumor antigen steadily increases the expression level of PD-1.¹¹
- Persistent expression of PD-1 on T cells induces T-cell exhaustion and loss of effector functions, such as proliferation, cytotoxicity, and survival.1
PD-L1 protein is commonly overexpressed in solid tumors.¹⁰
In general, improved response to PD1/PD-L1 inhibitors tends to correlate with patient tumors having:^8,12,14,16
- Higher PD-L1 protein expression
- Higher mutational load or tumor mutational burden (TMB)
- Higher mismatch repair deficiency (MMR) and microsatellite instability (MSI)
- Earlier line of therapy
Many kinds of genomic aberrations, such as the copy number amplification of the genes PD-L1 and JAK2 can result in high expression of PD-L1 protein and poor prognosis; however, the actual response to PD-1/PD-L1 antagonistic inhibition does not necessarily follow this biomarker pattern.^12,14

Non-small cell lung cancer(NSCLC)

Anti-PD-1/PD-L1 therapies for NSCLC tend to use PD-L1 protein expression to select patients because response rates are higher in PD-L1-expressing tumors relative to unselected populations.^14,15
In general, PD-1/PD-L1-inhibiting therapies show more benefit in smokers versus non-smokers; however, evidence suggests that the higher ORR is likely due to the higher tumor mutational burden (TMB) associated with the smoking population.¹⁵
Randomized phase 3 trials have indicated that patients carrying EGFR or ALK mutations exhibit less efficacy of anti-PD-1/PD-L1 treatment than those with wild-type, whereas KRAS mutations are likely to be predictors of favorable outcomes.^12,17

Head and neck squamous cell carcinoma (HNSCC)

A statistically significant increase in ORR was observed in patients with HNSCC treated with a PD-1 inhibitor in PD-L1-positive (22%) versus PD-L1-negative (4%) tumors.¹⁴
In HNSCC, smoking seems to contribute to a more immunosuppressive tumor microenvironment (TME) and negatively impact anti-PD-1/PD-L1 efficacy.¹⁸
Increased TMB and neoantigen load have been shown to correlate with response to anti-PD-1/PD-L1 therapies in HPV- HNSCC; however, most of the studies conducted to date have refuted their predictive value in HPV+ patients.¹⁸

RESISTANCE

Up to 60% of patients across different tumor types display primary resistance to anti-PD-1/PD-L1 agents.¹⁸
Several mechanisms have been suggested such as poor tumor immunogenicity, limited intratumoral immune cell infiltration, coexpression of multiple inhibitory receptors, and induction of immunosuppressive pathways within the TME.¹⁸
To overcome resistance, many ongoing clinical trials are evaluating combination strategies with other immunotherapies, targeted agents, chemotherapy and radiotherapy.¹⁸

Related Research

Immuno-Oncology

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PTPN2/N1

CD39

CCR8

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