Can PBMCs be used as a tool for the identification of immune biomarkers in lung cancer?

Lung cancer is a leading cause of cancer-related deaths worldwide, with treatment responses varying widely among patients.

Dr. Carminia Maria Della Corte from the University of Texas MD Anderson Cancer Center is at the forefront of research into using peripheral blood mononuclear cells (PBMCs) to identify immune biomarkers. Her work explores the cGAS/STING pathway, DDR gene mutations, and advanced 3D tumour models, offering insight into predicting immunotherapy responses and tailoring treatments for non-small and small cell lung cancer.

Read the original research: doi.org/10.3390/biomedicines12040809

Transcript

Hello and welcome to Research Pod where we dive into ground-breaking advances in science and modern medicine. Thank you for listening and joining us today. In this episode we explore the remarkable work of Dr Della Corte, a postdoctoral research fellow at the University of Campania Luigi Vanvitelli’s Department of Precision Medicine. Dr Della Corte is renowned for her extraordinary contributions in developing targeted treatments, particularly in lung cancer.

Lung cancer can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) and can be differentiated by the appearance of the cancer cells, and the growth of the cancer. Over the years, chemotherapy and immunotherapy, particularly in combination have evolved. Immunotherapy essentially optimises cells of your immune system using targeted therapy to better equip them in their fight against cancer. Immunotherapies, particularly immune checkpoint inhibitors like anti PD-L1/PD-1 have revolutionised cancer treatment and is now the standard of care for patients with lung cancer, which is used alone or in combination with chemotherapy. These inhibitors bind to the PD-L1, a protein expressed on tumour that disables the immune system cancer killing white blood cells called T cells. 

While these treatment combinations have advanced our treatment landscape in non-small and small cell lung cancer, their effectiveness varies among patients. Some patients respond well, while others experience only temporary effects or none at all. Currently, PD-L1 expression is the only target and biomarker in selecting patients for immunotherapies in non-small and small cell lung cancer. There is an unmet need in these patients to identify reliable biomarkers that can predict how well patients will respond to these treatments, this is of particular interest in lung cancer as biopsy material is hard to obtain from patients with lung cancer. 

Dr Della Corte and her team are pioneering innovative approaches in the fight against lung cancer, and primarily focusing on how peripheral blood mononuclear cells (PBMCs) could be a useful tool in biomarker discovery, which could revolutionise our ability to predict immune and treatment responses. 

PBMCs are white blood cells derived from blood samples and include other immune cells like T cells and natural (NK) cells. Their accessibility and role in the immune response in the fight against cancer make them a promising tool for studying cancer-related immune pathways. Dr Della Corte’s study enrolled 28 patients with NSCLC or SCLC, treated with chemotherapy (cisplatin) and/or PD-L1 inhibitors including atezolizumab and durvalumab. 

A major focus of the research was the cGAS/STING pathway, a critical component of the immune response. Dr Della Corte’s research team previously reported that cGAS/STING pathway activation can predict how effective immunotherapy response in patients with lung cancer, as STING activation is known to be a mediator of PD-1 expression. When activated, chemical messengers or chemokines

CXCL10 and CCL5 are released to orchestrate immune defences. There is a lot of evidence that supports CXCL10 and CCL5 expression as a potential biomarker, in this study these markers were predictive of worsened outcome. In patients who responded well to treatment known as “best responders” had significantly higher expression of the cGAS/STING pathway including CXCL10 and CCL5. Conversely, non-responders, had notably lower levels of these markers, suggesting a weakened immune activation, which was indicative of poor response to anti-PD-L1 treatment. This pathway activation correlated with improved clinical outcomes, highlighting its potential as a predictive biomarker. 

It has been reported that 15% of patients with lung cancer have a mutation in DNA damage response (DDR) genes, these mutations impair the cell’s ability to repair DNA damage, making cancer cells more vulnerable to certain treatments. Accumulating evidence suggests that the cGAS-dependent STING pathway is typically activated in T cells by the presence of DNA damage, or by DNA damage response (DDR) gene changes in patients with NSCLC. Responding patients with NSCLC had more DDR mutations, particularly in genes called BARD1 and ATM. Interestingly, non-responding patients had no DDR mutations. Suggesting a link between DDR gene variants and treatment efficacy, however, further validation is required in larger patient cohorts. Findings from this study suggest that the presence of DDR variants in PBMCs may have an impact on their clinical response to immunotherapy, as patients without these mutations in this cohort were less responsive to treatment than those who had them. Testing for DDR mutations in PBMCs could refine patient selection for immunotherapy, tailoring treatments to those who are most likely to benefit. 

To explore potential treatment strategies, researchers tested DNA-PK-I, a DDR inhibitor on PBMCs, which works by interfering with the DNA damage response process. In non-responding patients DNA-PK-I significantly increased expression of the cGAS/STING pathway, reinvigorating immune responses in these cells. Suggesting that blocking this pathway is an important requirement for activation of immune responses in PBMCs. This could be due to the impact of treatment on the DDR machinery, or that the DDR machinery is altered in best responding and responding patients. Taken together, this could suggest that PBMCs from lung cancer patients could be useful in studying the activation of immune response pathways with drugs, like DDR inhibitors, and could be of interest as potential biomarkers if correlated with the presence of DDR gene mutations.

The study also utilized an advanced 3D tumour spheroid model to evaluate the functionality of PBMCs derived from patients with lung cancer. These miniature tumour environments allowed the team to observe interactions between the immune cells and cancer when given cisplatin. Immune cells treated with cisplatin or DNA-PK-I successfully were able to infiltrate the tumour and destroy these tumours from within. This innovative approach of using PBMCs offers a valuable alternative to animal models, enable more precise studies of immune responses and drug efficacy. DNA-PK-I could also open new treatment options in patients who do not respond to anti-PD1/PD-L1 antibodies, or other immunotherapies.

Dr Della Corte and her team, wanted to determine what subset of PBMCs were more involved in the cGAS/STING activation. Further analysis revealed that CD8+ T cells and NK cells, both key players in cancer killing had significantly greater STING expression particularly in best responding and responding cohorts of patients with lung cancer. These cells also produced elevated levels of cytotoxic proteins like perforin, granzymes A and B, and granulysin, which are crucial for attacking tumours. 

Current methods for biomarker analysis, like biopsies, are invasive and often fail to capture the dynamic nature of immune responses. PBMCs offer a non-invasive repeatable alternative. This study highlights their potential to predict immune system activation in response to therapies, serving as a tool for testing drugs like DDR inhibitors, and helping to expand the toolkit for identifying promising immune biomarkers like CXCL10, CCL5 and DDR mutations. 

In summary, Dr Della Corte envisions larger patient studies to help validate these findings and refine the use of PBMCs in a clinical setting. Dr Della Corte and her team says that their work has taken an important step towards integrating potential use of PBMCs as predictive tools, using their ability to highlight possible biomarkers such as DDR mutations and STING pathway-associated genes in treatment of non-small cell lung cancer. She hopes to expand her research into larger patient populations to validate findings and to introduce new tools into the treatment of non-small and small cell lung cancer, paving the way for new possibilities in lung cancer care, advancing the field of precision medicine

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