Pan-immune-inflammation in colon cancer: A prognostic biomarker and the role of tumor location in personalized care

Abstract

Despite advances in surgery, chemotherapy, and radiotherapy, the treatment of colorectal cancer (CRC) requires more personalized approaches based on tumor biology and molecular profiling. While some relevant mutations have been associated with differential response to immunotherapy, such as RAS and BRAF mutations limiting response to anti-epithelial growth factor receptor drugs or microsatellite instability predisposing susceptibility to immune checkpoint inhibitors, the role of inflammation in dictating tumor progression and treatment response is still under investigation. Several inflammatory biomarkers have been identified to guide patient prognosis. These include the neutrophil-lymphocyte ratio, Glasgow prognostic score (GPS) and its modified version, lymphocyte-C-reactive protein ratio, and platelet-lymphocyte ratio. However, these markers are not yet included in the standard clinical management of patients with CRC, and further research is needed to evaluate their efficacy in different patient populations. A recent study by Wang et al, published in the World Journal of Gastroenterology, sheds light on the prognostic significance of pan-immune-inflammation value (PIV) in CRC, particularly concerning primary tumor location. Specifically, the authors found that a high PIV was strongly correlated with worse disease-free survival in patients with left-sided colon cancer, whereas no such association was observed in patients with right-sided colon cancer. Integrating tumor location into the prognostic assessment of CRC may improve our ability to more accurately identify high-risk patients and develop personalized treatment plans that are more likely to improve patient outcomes.

Key Words: Colorectal cancer; Inflammatory biomarkers; Tumor location; Targeted therapy

Core Tip: A recent study by Wang et al highlights that a high pan-immune inflammation value is associated with worse disease-free survival in left-sided colon cancer, but not in right-sided colon cancer. This suggests that considering tumor location in colorectal cancer prognosis may help identify high-risk patients and more effectively tailor treatment plans.

INTRODUCTION

Colorectal cancer (CRC) is the third most common cancer worldwide and a leading cause of cancer-related deaths[1]. Despite advances in surgery, chemotherapy, and radiotherapy, the limitations of these treatments underscore the urgent need for more personalized approaches[2]. Biomarkers, biological molecules that hold the key to unlocking a new era of precision in CRC care, are emerging as critical tools in this regard[3,4].

BIOMARKERS: A NEW ERA OF PRECISION IN CRC

Molecular profiling: Unmasking the tumor's identity

Genetic and epigenetic alterations drive the development and progression of CRC. Unraveling the unique molecular profile of the tumor through biomarker analysis is critical for guiding treatment decisions, particularly in advanced or metastatic disease[3]. In particular, the mutational profile of the tumor can predict the response to epithelial growth factor receptor (EGFR)-targeting monoclonal antibodies, such as cetuximab and panitumumab, which have been validated over the past 20 years as powerful tools for prolonging survival in patients with metastatic CRC[5].

Key players in this molecular landscape include RAS mutations (KRAS, NRAS) and BRAF mutations, particularly the V600E mutation, which confer resistance to anti-EGFR therapies and are associated with poorer prognosis[3,6,7]. Similarly, human epidermal growth factor receptor 2 (HER2) amplification, although relatively rare in CRC, can drive tumor growth and predict resistance to anti-EGFR therapies. However, anti-HER2 therapies, initially successful in treating HER2-positive breast cancer, are now showing promise in HER2-amplified metastatic CRC[3,8]. Finally, microsatellite instability-high (MSI-H) tumors have a distinct molecular profile characterized by a high number of mutations and neoantigens, making them particularly susceptible to immune checkpoint inhibitors (ICIs), a major breakthrough in CRC treatment[9]. These drugs, which block inhibitory signals that suppress the immune system, have demonstrated remarkable efficacy in patients with MSI-H/dMMR CRC, resulting in durable responses and improved survival[9,10]. Unfortunately, the majority of CRC tumors are microsatellite stable or mismatch repair proficient, rendering them less responsive to ICIs[11]. This is largely due to their lower tumor mutational burden and weaker immunogenicity, making them adept at evading immune surveillance[9,12]. Overcoming this immune evasion is a major focus of ongoing research, with strategies exploring combinations of ICIs with other treatment modalities, such as chemotherapy, targeted therapies, and radiotherapy[9,12].

Inflammation: A silent partner in CRC progression

Chronic inflammation plays a critical role in the development and progression of CRC, influencing tumor growth, angiogenesis, and metastasis[2]. In recent years, several studies have linked inflammation to postoperative recurrence in patients undergoing curative surgery for CRC. For example, Matsubara et al[13] found that high post-resection C-reactive protein (CRP) levels were linked to significantly worse recurrence-free survival in 467 patients with stage I–III CRC who underwent curative surgery. Similarly, Di Caro et al[14] discovered that high preoperative serum levels of inflammatory cytokines and the acute-phase protein Pentraxin-3 were associated with an increased risk of recurrence independently of TNM staging in 69 patients. Consequently, several inflammation-related biomarkers, readily available through routine blood tests, have emerged as valuable prognostic indicators[2]. Elevated neutrophil-lymphocyte ratio, reflecting a higher proportion of neutrophils to lymphocytes, is consistently associated with poorer prognosis in CRC[2,4,15]. The Glasgow prognostic score and its modified version incorporate serum CRP and albumin levels, reflecting both systemic inflammation and nutritional status, with higher scores linked to worse outcomes[2,4,16]. A low lymphocyte-CRP ratio, indicating a lower proportion of lymphocytes to CRP, is associated with poorer prognosis and increased risk of postoperative complications[2,17]. Elevated platelet-lymphocyte ratio, reflecting a higher proportion of platelets to lymphocytes, is linked to poorer prognosis in CRC, particularly in advanced stages[2,18]. While these biomarkers hold significant promise, their optimal cutoff values and clinical application remain areas of active investigation. Multicenter prospective studies are crucial to standardize their use and maximize their clinical utility[2].

The crucial role of inflammation in CRC should also be viewed as a driver of oncogenic mutations. For example, KRAS mutations are more commonly present in CRC arising from chronic inflammatory disease. Conversely, these mutations have been shown to create an immunosuppressive tumor microenvironment (TME), suppressing the expression of pro-inflammatory cytokines. Therefore, there is a complex and yet unclear link between chronic inflammation, the development[19] of oncogenic mutations, and the immunomodulation of the TME. Understanding this intricate relationship may lead to many interesting developments in personalized therapy in the next few years.

PAN-IMMUNE-INFLAMMATION VALUE AS A LOCATION-SPECIFIC BIOMARKER

A recent study by Wang et al[20], published in the World Journal of Gastroenterology, sheds light on the prognostic significance of the pan-immune-inflammation value (PIV) in colon cancer, particularly in relation to primary tumor location. This research is a pivotal contribution to our understanding of the complex interactions between systemic inflammation and tumor biology in CRC.

The distinction between left-sided colon cancer (LCC) and right-sided colon cancer (RCC) has been well established, with each subtype exhibiting distinct clinical, pathological, and molecular characteristics[21]. The study by Wang et al[20] adds to this narrative by demonstrating that the prognostic utility of PIV is significantly influenced by tumor location within the colon. Specifically, the authors found that a high PIV was strongly correlated with poorer disease-free survival in patients with LCC, whereas no such association was observed in patients with RCC.

The implications of these results are profound, suggesting that the prognostic value of systemic inflammatory response markers, such as PIV, may not be universally applicable across all colon cancer subtypes. Instead, the efficacy of these biomarkers may vary depending on tumor location, necessitating a more nuanced approach to their clinical application. In patients with LCC, a high PIV could serve as a critical indicator of poor prognosis and guide more aggressive and tailored treatment strategies. Conversely, the lack of a significant correlation between PIV and disease-free survival in patients with RCC highlights the need for further research to identify more relevant prognostic markers for this subgroup.

The uncertainty surrounding the prognostic value of PIV in RCC may be attributed to the distinct characteristics of the TME inherent to tumor location. RCCs exhibit a higher prevalence of KRAS and BRAF mutations. In contrast, TP53 mutations are more frequently observed in LCC. These genetic alterations contribute to an immunosuppressive TME, influencing tumor behavior and patient outcomes.

Furthermore, MSI-H tumors, which are more prevalent in RCC, exhibit an augmented inflammatory response and an enhanced recognition by the immune system, rendering them more responsive to immunotherapy. Consequently, elevated circulating inflammatory biomarkers may potentially predict a patient’s response to treatment. In rectal cancer, increased neutrophil-lymphocyte ratio and platelet-lymphocyte ratio before neoadjuvant chemoradiotherapy have been linked to poorer prognosis in patients with MSI-H. While this correlation has yet to be demonstrated in patients with colon cancer, it presents promising avenues for future research. Therefore, genetic, molecular, and inflammation-related characteristics should be considered when designing personalized therapies for patients with CRC. Further investigation is warranted to elucidate the relationship between inflammation and TME characteristics across different tumor locations and to understand the potential prognostic roles of inflammatory markers in CRC[22-24].

The large sample size and rigorous methodology of the study by Wang et al[20] lend credibility to its conclusions and strongly support integrating tumor location into the prognostic assessment of colon cancer. This integration could improve our ability to more accurately identify high-risk patients and develop personalized treatment plans that are more likely to improve patient outcomes. However, the study also raises important questions about the underlying mechanisms driving the observed differences in the prognostic value of PIV between LCC and RCC. The role of various immune and inflammatory cells in the TME, as well as their interaction with tumor cells, may differ significantly between these subtypes, influencing the overall prognostic landscape. The role of TME in influencing tumor behavior has already been studied in rectal cancer, particularly in relation to response to neoadjuvant treatment, and immunological and molecular differences in different populations have been associated with different prognoses[25,26]. Further research is needed to elucidate these mechanisms and to explore whether other systemic inflammatory response markers may also have site-specific prognostic value.

Furthermore, it should be noted that the study by Wang et al[20] is not without limitations, as acknowledged by the authors themselves. Notably, the absence of data on molecular mutations—specifically RAS mutations—and the lack of information regarding adjuvant therapy limit the applicability of their results. These gaps highlight the need for further research to validate and expand upon their findings.

FUTURE DIRECTIONS: TOWARDS A CONTINUUM OF PERSONALIZED CARE

Recent studies have highlighted the crucial function of inflammation in the genesis and recurrence of colon cancer, prompting a shift toward the investigation of novel targets for systemic therapy. Preclinical models have demonstrated encouraging outcomes with agents such as JAK inhibitors, chemokine receptor antagonists (e.g., CXCR2 inhibitors), antibodies targeting the interleukin-6 receptor or its signaling pathway, and cyclooxygenase-2 inhibitors[27]. The integration of these therapeutic modalities with chemotherapy and surgical interventions holds considerable potential to significantly improve the prognosis of patients with colon cancer.

The future of CRC care lies in a comprehensive, multiomics approach that integrates data from genomics, transcriptomics, proteomics, and metagenomics to create a holistic picture of the tumor and its microenvironment[3,28]. Liquid biopsies, which analyze circulating tumor DNA, offer the potential for real-time monitoring of tumor evolution and treatment response, further refining personalized treatment strategies[3,29]. The integration of artificial intelligence could enhance the clinical application of whole-genome sequencing analysis, enabling more precise therapeutic decision-making and improving patient prognosis[30].

CONCLUSION

The study by Wang et al[20] represents a significant advancement in our understanding of the role of PIV as a prognostic biomarker in CRC. By highlighting the importance of tumor location, this research paves the way for more precise and personalized approaches to CRC treatment. As we continue to explore the molecular and inflammatory landscape of CRC, the integration of such biomarkers into clinical practice will be critical to improving patient outcomes and advancing the field of precision medicine in oncology.

Biomarkers are changing the landscape of CRC care, shifting the focus beyond the limitations of traditional approaches toward a future of precision medicine. By unlocking the molecular secrets of the tumor and harnessing the power of the immune system, we can tailor treatment strategies to individual patients, maximizing their chances of survival and improving their quality of life. As the field advances, the integration of studies like Wang et al’s will be critical to refining and expanding our arsenal of prognostic tools, ultimately improving patient care and outcomes[20].