Biomarker-driven insights into immune checkpoint inhibitor therapy in small-cell lung cancer
Shuxing Wang1, Xinrui Zhao1, Yue Zeng2
1Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China.
Abstract:
Small cell lung cancer (SCLC) is an aggressive malignancy with limited treatment options, and the integration of immune checkpoint inhibitors (ICIs) into treatment regimens has reshaped the therapeutic landscape. However, challenges such as rapid resistance and lack of effective predictive biomarkers remain. This review highlights the pivotal roles of biomarkers in SCLC, underscoring their contributions to treatment resistance across tumor-intrinsic mechanisms, immune landscape of the tumor microenvironment (TME) and systemic host factors. Tumor-intrinsic features, including molecular subtypes, genetic alterations such as TP53 and RB1 mutations, and tumor mutation burden (TMB), have shown varying associations with ICI efficacy. Notably, the SCLC-I (inflamed) molecular subtype appears more responsive to immunotherapy. Within the TME, programmed cell death ligand 1 expression, tumor-infiltrating lymphocytes (TILs), regulatory T cells, myeloid-derived suppressor cells, and tissue-associated cytokines and chemokines contribute to immune modulation. High CD8+ TILs are linked to better outcomes, while increased immunosuppressive populations often suppress anti-tumor response. Systemic factors, encompassing tumor-derived (ctDNA, CTCs, tumor-derived EVs) and host-derived (circulating immune cell phenotypes, MHC expression, immune profile, baseline clinical characteristics) components, and psychological factors, provide valuable insights into treatment response and prognosis. Further research is needed to validate biomarkers and investigate combination approaches to overcome resistance, offering hope for improved patient outcomes in SCLC.
Insights
Biomarkers are crucial for understanding treatment resistance in small cell lung cancer (SCLC). Identifying these biomarkers can help overcome resistance to immune checkpoint inhibitors (ICIs) and improve patient outcomes.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Small cell lung cancer (SCLC) is an aggressive cancer with limited treatment options.
- Immune checkpoint inhibitors (ICIs) have advanced SCLC treatment, but resistance remains a challenge.
- Effective predictive biomarkers are needed to guide ICI therapy in SCLC.
Purpose of the Study:
- To review the role of biomarkers in SCLC treatment resistance.
- To explore tumor-intrinsic, tumor microenvironment (TME), and systemic host factors influencing ICI efficacy.
- To highlight potential strategies for overcoming resistance in SCLC.
Main Methods:
- Literature review focusing on biomarkers in SCLC and ICI resistance.
- Analysis of tumor-intrinsic features (molecular subtypes, mutations, TMB).
- Evaluation of TME components (PD-L1, TILs, immune cells, cytokines) and systemic factors (ctDNA, CTCs, host immunity).
Main Results:
- Tumor-intrinsic features like the SCLC-I subtype and specific mutations impact ICI response.
- TME factors, including CD8+ TILs and immunosuppressive cells, modulate anti-tumor immunity.
- Systemic factors from tumor and host offer insights into treatment response and prognosis.
- High CD8+ TILs correlate with better outcomes, while immunosuppressive cells hinder response.
Conclusions:
- Biomarkers are critical for predicting and overcoming ICI resistance in SCLC.
- Understanding tumor-intrinsic, TME, and systemic factors is key to personalized SCLC treatment.
- Further research and combination therapies are needed to improve SCLC patient outcomes.
