Immunotherapy for small cell lung cancer: mechanisms of resistance

ABSTRACT

Introduction: Small cell lung cancer (SCLC) is a highly malignant disease with a dismal prognosis that is currently being tested for theclinical activity of checkpoint inhibitors. SCLC is associated with smoking and exhibits a high mutational burden. However, low expression of PD-L1 and MHC antigens, as well low levels of immune cell infiltration and rapid tumor progress seems to limit the efficacy of anticancer immunity. Nevertheless, long-term survival was reported from studies using anti-PD-1/PD-L1 and CTLA-4 agents.

Areas covered: Data of clinical trials of checkpoint inhibitors in SCLC show lower success rates compared to NSCLC. The mechanisms of resistance to immunotherapy are discussed for their relevance to SCLC patients.

Expert opinion: Although some factors, such as a high mutation rate, favor immunotherapy for SCLC patients, downregulation of MHC class I, low expression of PD-L1, poor tumor infiltration by effector T cells, presence of myeloid-derived suppressor cells as well as regulatory T lymphocytes counteract the immune system activation by checkpoint inhibitors. Furthermore, this tumor develops avascular regions which have immunosuppressive effects and restrict access of lymphocytes and antibodies. In conclusion, immunotherapy in SCLC is effective in highly selected patients with good performance status and special and unknown preconditions contributing to long-lasting responses.

KEYWORDS:

• Small cell lung cancer
• immunotherapy
• checkpoint inhibito
• PD-L1
• tumor microenvironment

Article highlights

• ED-SCLC is treated with chemotherapy resulting in poor survival.

• Checkpoint inhibitor trials in SCLC show less activity compared to NSCLC.

• SCLC has a high mutation load and should be sensitive to immunotherapy.

• Low MHC and PD-L1 expression, suppressive immune cells and low rates of tumor infiltration limit the effects of checkpoint inhibitors.

• Rapid growth of SCLC generates avascular regions for immune evasion.

• Circulating tumor cell (CTC) spheroids lacking PD-L1 survive.

• Effective immunotherapy of SCLC needs supplementary strategies to checkpoint inhibitors.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.