Splenic index score as a predictor of results in metastatic patients with non -cell lung cancer cancer treated with immune -checkpoint inhibitors

This study showed that the Milzinex score, calculated by multiplying the spleen volume and NLR, before the Nivolumab treatment in patients with MNSCLC who had advanced after chemotherapy could be a predictive marker for survival. It was found that a high spleen index score that was calculated before the treatment of Nivolumab is statistically associated with shorter OS and PFS, regardless of the PD-L1 status.

Earlier preclinical and clinical studies have shown that an increased spleen volume as an indirect marker for increased serum -MDSC mirror can serve and can be connected to immunotherapy resistance^6.12.13. In mouse cancer models, the enlargement of spleen is observed due to an extramedullary hematopoies and the accumulation of a heterogeneous population of unripe myeloic cells, which are recognized as myeloid suppressor cells (MDSC). In cancer patients, the spleen serves as a significant reservoir for MDSCs, which accumulates these cells and thereby plays an immunosuppressive role. While lymphoid tissue typically resist MDSC infiltration^14.15.16. Ce Tavukçuoğlu and colleagues showed this phenomenon in their human study. Music samples of cancer patients have shown a significant accumulation of MDSC with simultaneous suppression of the t cell function, which indicates this¹⁷. Despite his promising role in understanding the immune response, it is not yet widespread in clinical practice.

Numerous clinical studies have also shown the connection between peripheral inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) and the resistance to immunotherapy¹⁸. Despite this findings, there was no final consensus regarding the use of NLR as an independent predictive biomarker. In view of these complexities, our study tried to close this gap by integrating these two biomarkers – a splenish volume as a proxy for the MDSC accumulation and NLR as a marker for systemic inflammation – into a new composite. This approach is the first of its kind that shows that this combined score is significantly associated with the survival results in patients with metastatic non-small cell lung cancer (NSCLC), which offers a promising instrument to predict patient forecast in the context of immunotherapy.

We would like to emphasize that an important mechanism of immune resistance to ICI-based therapy in patients with tumor-associated chronic inflammation is the increase in MDSC cells that can be easily identified by increasing the spleen volume. In addition, the neutrophil-to-lymphocyte ratio (NLR) is a well-established peripheral marker for chronic inflammation, whereby a significant part of the literature supports its relevance^19.20.21. In this study, we selected NLR as the primary systemic inflammatory marker due to its established prognostic importance in malignant diseases, especially in the context of immunotherapy. While both NLR and PLR showed significant associations, NLR showed a greater prediction value, probably due to the more direct reflection of the balance between systemic inflammation and antitum time immunity¹⁴. Although the Milzindex score calculated using the PLR ​​provided statistically similar results, we preferred NLR due to its stronger prognostic relevance and wider clinical applicability.

In chronic inflammation, cytokines such as interleukin-1β (IL-1β) promote the expansion of myeloid suppressor cells (MDSCs) that support tumor progression and contribute to resistance to immune-checkpoint inhibitors (ICIS) by suppressing the function of T cells and natural kilter cells. MDSCs also activate regulatory T cells (TREGs), which increase the production of immunosuppressive cytokines such as interleukin-10 (IL-10), which affects CD4 + and CD8 + T cell functions and promoted tumor growth²². In accordance with these results, our study observed that patients with an increased spleen volume and high NLR, which reflect a high spleen index score, had the poorest survival results.

In several studies in the literature, the relationship between the base molic volume, NLR and the reaction to immunotherapy were examined. Loïck Galland and colleagues found that the metastatic NSCLC -Messeline volume treated with ICIS, which began in patients with metastatic NSCLC before the start of immunotherapy, was connected to overall survival (OS). They primarily related this finding to chronic inflammation⁹. Joao V Alessi and colleagues identified a significant relationship between NLR with a low base and OS and PFS at NSCLC²³. C Valero and colleagues showed a strong connection between the basic NLR and survival in patients who undergo immunotherapy¹⁸. M Hwang and colleagues showed a strong relationship between NLR and immunotherapy reaction²⁴. S Anpalakhan and colleagues found that a group of patients who received immunotherapy, including patients with NSCLC, were associated with better clinical reactions²⁵.

In contrast to these studies, our investigation showed that the basic line volume and the NLR mirror before initiating the Nivolumab treatment were statistically not significant predictors for survival if they were considered individually. However, it was found that the Milzintex score, which was generated by combining these laboratory and radiological parameters, is associated with survival regardless of the PD-L1 status before the start of Nivolumab.

A study that supported our results³. In our study, we observed that the group accompanies bad OS and PFS with a high Milz index score with a high NLR.

Some studies that examined the connection between spleen volume and survival have found no statistically significant connection between the volume of treatment and survival. For example, Francesca Castagnoli et al. found no predictive or prognostic value of changes in the spleen volume in patients with advanced NSCLC treated with Pembrolizumab²⁶.

Susok et al. examined the influence of immunotherapy on the spleen volume in patients with advanced melanoma and found a significant increase in median spleen volume three months after treatment with ICIS compared to the starting value, although no correlation with the clinical results was determined²⁷. Similarly, Lukas Müller et al. reported on an increase in the spleen volume after the beginning of immunotherapy with a significant number of hepato cellular carcinoma patients (HCC) who underwent first-line treatment. However, this increase was not connected to the survival results and was mainly due to portal hypertension than to the immune modulation²⁸. In contrast to these studies, we have created a score by combining a strong peripheral indicator of tumor -associated chronic inflammation, with spleen volume. We found that a high spleen index score that was derived from this combined evaluation was associated with bad PFS and OS.

The spleen index score primarily seems to be a prognostic biomarker, since it is significantly associated with OS and PFS regardless of PD-L1 status and reflects systemic inflammation and MDSC-controlled immunosuppression. However, his potential predictive value cannot be overlooked, since it can help to help patients less likely to benefit from Nivolumab, which depends on a role in the treatment layering. In order to establish its predictive benefits, future studies should compare and untreated cohorts to determine whether the score specifically influences the response to immunotherapy instead of just reflecting the overall burden and inflammation of the entire disease burden.

Several restrictions on our study must be discussed. First, it was retrospective nature. The sample size was low, and all patients received the second line and the subsequent therapy in Nivolumab due to reimbursement rules in Turkey. Due to the retrospective design of our study, no serum samples from this period were available, which determined the simultaneous measurement of MDSCs and the ratings of the Milzintex. In addition, our patient population was heterogeneous, including tumors with different PD-L1 expression levels, and all patients had previously subjected to at least one line of systemic chemotherapy that could have influenced the spleen volume and peripheral immune cell profiles. While existing studies have evaluated the NLR and the spleen volume individually in relation to the reaction of immunotherapy, the examination of their combined use is missing. Our hypothesis was that the multiplication of these two biomarkers would result in a more effective prognostic indicator. This study is pioneering work when it is one of the first to combine radiological and peripheral inflammatory biomarkers to assess the second and subsequent treatments in metastatic NSCLC and thus make a significant contribution to the field.