Chronic inflammation is considered a major risk factor for cancer formation. Inflammation within the tumor environment plays a role in its response to therapy, growth, and prognosis. Cancer associated inflammation is known to occur in the tumor microenvironment and in the systemic circulation, and is correlated with disease progression and prognosis in many cancers. Blood cells such as neutrophils, lymphocytes, platelets, and circulating proteins such as C-reactive protein, and interleukins, such as IL-6, have been associated with inflammatory responses, which contribute to tumorigenesis. Cancer has found ways to evade the immune response; a pathway that can attenuate the innate immune response is via blocking immune checkpoints. Development of monoclonal antibodies against inhibitory immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have given rise to immunotherapy, which has shown remarkable responses in anti-tumor activity resulting in several U.S. Federal and Drug Administration (FDA)-approved checkpoint inhibitors.
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Chronic inflammation has been well-accepted to play a considerable role in carcinogenesis [1]. In fact, this relationship has been explored since the 19th century when Virchow found that there are leukocytes in tumor tissues and proposed a potential relationship between tumor and inflammation [2]. About a quarter of cancer cases may be due to infection and chronic inflammation [3]. The tumor microenvironment (TME) and immune system play a role in the occurrence and development of malignancies. Neutrophils act as effectors of both innate immunity and cell signaling in adaptive immune response and inhibit the activity of cytotoxic T lymphocytes in vitro. These also secrete tumor growth factors, cytokines, chemokines, such as TGF-beta, vascular endothelial growth factor (VEGF), IL-6, IL-8, IL-12, and matrix metalloproteinases which induce angiogenesis, supporting tumor growth [4,5]. Tumor cells also release granulocyte colony-stimulating factor which can increase the number of neutrophils. Monocytes differentiate into macrophages or dendritic cells in the tissue microenvironment. Platelets contribute to inflammation by releasing VEGF, which mediates the migration and extravasation of leukocytes, and platelet-derived growth factor (PDGF). T-lymphocytes in the TME have also been associated with improved clinical outcomes in patients affected by malignancies. T-lymphocytes can recognize and kill tumor cells which can affect proliferation and thereby further spread of disease.
Immune checkpoint inhibitors (ICIs), which are a form of immunotherapy, have been approved by the U.S. Federal and Drug Administration (FDA) as a treatment option for a variety of malignancies due to their durable clinical benefit in terms of treatment response and relatively favorable toxicity profile for patients.
In 2011, ipilimumab, which targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), was approved by the U.S. FDA for the treatment of cancer after demonstrating improved overall survival (OS) in patients with metastatic melanoma [6,7]. Eventually, other ICIs such as pembrolizumab resulted in longer OS compared to ipilimumab in metastatic melanoma. In advanced non-small cell lung cancer (NSCLC), pembrolizumab also fared better and demonstrated better progression free survival (PFS) and OS compared to platinum-based chemotherapy [8].
As of 2020, a total of seven immuno-oncology (IO) agents have been approved, including ipilimumab, which targets CTLA-4, atezolizumab, avelumab, and durvalumab, which target programmed cell death ligand 1 (PD-L1), and nivolumab, pembrolizumab, and cemiplimab, which target programmed cell death 1 (PD-1). These agents have been approved for numerous types of cancer such as melanoma, NSCLC, head and neck squamous cell malignancies, liver, urothelial, renal cell, gastric, breast, and colorectal cancers. Additional IO agents are currently under investigation [7], and Table 1 lists the currently approved ICI agents.
Name | Target | Year of Approval | Malignancies Approved for |
---|---|---|---|
Atezolizumab | PD-L1 | 2016 | urothelial carcinoma |
2020 | non-small cell lung cancer | ||
Avelumab | PD-L1 | 2017 | Merkel cell carcinoma |
2019 | renal cell carcinoma | ||
2020 | urothelial carcinoma | ||
Durvalumab | PD-L1 | 2017 | urothelial carcinoma |
2018 | non-small cell lung cancer | ||
Cemiplimab | PD-1 | 2018 | cutaneous squamous cell carcinoma |
2021 | basal cell carcinoma | ||
2021 | non-small cell lung cancer | ||
Ipilimumab | CTLA-4 | 2011 | melanoma |
2018 | renal cell carcinoma | ||
2018 | MSI-H/dMMR colorectal cancer | ||
Pembrolizumab | PD-1 | 2014 | melanoma |
2015 | non-small cell lung cancer | ||
2016 | head and neck cancer | ||
2017 | microsatellite instability-high/mismatch repair solid tumors | ||
2017 | gastric cancer | ||
2018 | Hodgkin’s lymphoma | ||
2018 | urothelial carcinoma | ||
2018 | cervical cancer | ||
2018 | hepatocellular carcinoma | ||
2018 | Merkel cell carcinoma | ||
2019 | renal cell carcinoma | ||
2019 | small cell lung cancer | ||
2019 | esophageal carcinoma | ||
2019 | endometrial cancer | ||
Nivolumab | PD-1 | 2014 | melanoma |
2015 | non-small cell lung cancer | ||
2015 | renal cell carcinoma | ||
2016 | Hodgkin’s lymphoma | ||
2016 | head and neck cancer | ||
2017 | urothelial carcinoma | ||
2017 | microsatellite instability-high/mismatch repair solid tumors | ||
2017 | hepatocellular carcinoma | ||
2018 | small cell lung cancer |
Considerable effort has been made towards identifying biomarkers of response to immunotherapy as predictive and prognostic markers since the use of these IO agents has increased in the past few years in oncology. Only 15–60% patients respond as expected to ICIs and can experience immune related adverse events [9]. Identifying biomarkers for this particular patient population is crucial.
Reduction in lymphocyte count can decrease anti-tumor response and affect ICI effectiveness as ICIs rely on the inhibitory signal function of T lymphocytes. Increased lymphocyte infiltration in the TME is associated with better prognosis and response to immunotherapy [10,11]. Given this, neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) have been used as inflammatory markers to predict outcomes in various malignancies. Measurement of these cells is simple and conveniently conducted on a complete blood count with differential from blood.
CRP is another serum inflammatory marker that has been studied in numerous infections and used as a biomarker in cancer. Elevated CRP levels have been shown to be associated with increased risk of cancer [47]. In addition, elevated CRP levels have been shown to also associate with cancer progression and decreased survival [48,49,50,51]. Harris et al. formally assessed CRP as a time-dependent prognostic variable for OS in patients treated with targeted therapy for clear cell and non-clear cell mRCC and that time-dependent effects are seen as representation of the intensity of systemic inflammation which can serve as a prognostic biomarker for mRCC [52]. Both pre-treatment and indeed post treatment CRP levels can help prognosticate survival after intervention in various genitourinary malignancies [53]. In patients with localized RCC who underwent nephrectomy, a prospective study looked at preoperative and postoperative CRP levels and found that postoperative CRP is the better predictor of metastasis and mortality following surgical resection [54].
High levels of baseline CRP have been associated with poor response to chemotherapy in various malignancies. As an acute phase protein of hepatic origin, CRP reflects the process of systemic inflammation from cancer and its related complications such as cachexia, pyrexia, and fatigue. In addition, higher CRP levels have been correlated with low levels of CD4+ T-cells, which play a key role in the antitumor immune response facilitated by immunotherapy [48,49,50,51].
Riedl et al. showed that elevated pretreatment CRP levels are associated with poor outcomes. Increase in CRP over time is a strong indicator of an elevated progression risk and on the contrary, decline in CRP is associated with treatment response. In conclusion, this study shows that CRP may serve as a simple biomarker for assessing and monitoring ICI treatment benefit in advanced NSCLC patients [55]. In a study of 95 patients with advanced melanoma treated with ipilimumab, decreased levels of CRP by the end of treatment were associated with better disease control and increased OS [56]. Brown et al. reported a retrospective analysis utilizing modified Glasgow prognostic score (mGPS) in 78 patients with mRCC treated with immunotherapy. The mGPS was developed as a scoring system predictive of clinical outcomes across multiple malignancies and incorporates inflammatory markers albumin and CRP. It was reported that a higher mGPS at baseline was associated with worse OS, and at six weeks as well, and hence, higher CRP values contributed to higher mGPS [57]. The same group of authors also reported, using mGPS in 53 patients with metastatic urothelial cell carcinoma, that higher mGPS was again correlated with shorter OS and high correlation with other inflammatory biomarkers, such as NLR, PLR, and MLR. Again, high CRP levels was seen in these patients with high mGPS [58].
This entry is adapted from the peer-reviewed paper 10.3390/biology10040325