Neutrophils play a key role in defence against infection and in the activation and regulation of innate and adaptive immunity. In cancer, tumour-associated neutrophils (TANs) have emerged as an important component of the tumour microenvironment. Here, they can exert dual functions. TANs can be part of tumour-promoting inflammation by driving angiogenesis, extracellular matrix remodelling, metastasis and immunosuppression. Conversely, neutrophils can also mediate antitumour responses by direct killing of tumour cells and by participating in cellular networks that mediate antitumour resistance. Neutrophil diversity and plasticity underlie the dual potential of TANs in the tumour microenvironment. Myeloid checkpoints as well as the tumour and tissue contexture shape neutrophil function in response to conventional therapies and immunotherapy. We surmise that neutrophils can provide tools to tailor current immunotherapy strategies and pave the way to myeloid cell-centred therapeutic strategies, which would be complementary to current approaches.

Neutrophil diversity and plasticity in tumour progression and therapy.

Liquid biopsies represent a potential revolution in cancer diagnostics as a noninvasive method for detecting and monitoring diseases, complementary to or even replacing current tissue biopsy approaches. Several blood-based biosources and biomolecules, such as cell-free DNA and RNA, proteins, circulating tumor cells, and extracellular vesicles, have been explored for molecular test development. We recently discovered the potential of tumor-educated blood platelets (TEP) as a noninvasive biomarker trove for RNA biomarker panels. TEPs are involved in the progression and spread of several solid tumors, and spliced TEP RNA surrogate signatures can provide specific information on the presence, location, and molecular characteristics of cancers. So far, TEP samples from patients with different tumor types, including lung, brain, and breast cancers, have been tested, and it has been shown that TEPs from patients with cancer are distinct from those with inflammatory and other noncancerous diseases. It remains to be investigated how platelets are "educated," which mechanisms cause intraplatelet RNA splicing, and whether the relative contribution of specific platelet subpopulations changes in patients with cancer. Ultimately, TEP RNA may complement currently used biosources and biomolecules employed for liquid biopsy diagnosis, potentially enhancing the detection of cancer in an early stage and facilitating noninvasive disease monitoring. Cancer Res; 78(13); 3407-12. ©2018 AACR.

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Tumor-Educated Platelets as a Noninvasive Biomarker Source for Cancer Detection and Progression Monitoring.

The emergence of immunotherapy has dramatically changed how non-small cell lung cancer is treated, and longer survival is now possible for some patients, even those with advanced disease. Although some patients achieve durable responses to checkpoint blockade, not all experience such benefits, and some suffer from significant immunotoxicities. Given this, biomarkers that predict response to therapy are essential, and testing for tumor programmed death ligand 1(PD-L1) expression is the current standard. The extent of PD-L1 expression determined by immunohistochemistry (IHC) has demonstrated a correlation with treatment response, although limitations with this marker exist. Recently, tumor mutational burden has emerged as an alternative biomarker, and studies have demonstrated its utility, irrespective of the PD-L1 level of a tumor. Gene expression signatures, tumor genotype (such as the presence of an oncogenic driver mutation), as well as the density of tumor-infiltrating lymphocytes in the tumor microenvironment also seem to affect response to immunotherapy and are being researched. Peripheral serum markers are being studied, and some have demonstrated predictive ability, although most are still investigational and need prospective validation. In the current article, the authors review the biomarker PD-L1 as well as other emerging and investigational tissue-based and serum-based markers that have potential to better predict responders to immunotherapy.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.32468

Biomarkers for immune checkpoint inhibition in non–small cell lung cancer (NSCLC)

Background: Immune checkpoint inhibition (ICI) with anti-CTLA-4 and/or anti-PD-1 antibodies is standard treatment for metastatic melanoma. Anti-PD-1 (pembrolizumab, nivolumab) and anti-PD-L1 antibodies (atezolizumab, durvalumab, avelumab) have been approved for treatment of several other advanced malignancies, including non-small-cell lung cancer (NSCLC); renal cell and urothelial carcinoma; head and neck cancer; gastric, hepatocellular and merkel-cell carcinoma (MCC); and classical Hodgkin lymphoma. In some of these malignancies approval was based on the detection of biomarkers such as PD-L1 expression or high microsatellite instability. Methods: We review the current status of prognostic and predictive biomarkers used in ICI for melanoma and other malignancies. We include clinical, tissue, blood and stool biomarkers, as well as imaging biomarkers. Results: Several biomarkers have been studied in ICI for metastatic melanoma. In clinical practice, pre-treatment tumor burden measured by means of imaging and serum lactate dehydrogenase (LDH) level is already being used to estimate the likelihood of effective ICI treatment. In peripheral blood, the number of different immune cell types such as lymphocytes, neutrophils, and eosinophils, as well as different soluble factors, have been correlated with clinical outcome. For intra-tumoral biomarkers, expression of the PD-1 ligand PD-L1 has been found to be of some predictive value for anti-PD-1-directed therapy for NSCLC and melanoma. A high mutational load, particularly when accompanied by neoantigens, seems to facilitate immune response and correlates with patient survival for all entities treated by use of ICI. Tumor microenvironment also seems to be of major importance. Interestingly, even the gut microbiome has been found to correlate with response to ICI, most likely through immuno-stimulatory effects of distinct bacteria. New imaging biomarkers, e.g. for PET, and MRI are also being investigated, and results suggest they will make early prediction of patient response possible. Conclusions: Several promising results are available regarding possible biomarkers for response to ICI, which need to be validated in large clinical trials. A better understanding of how ICI works will enable the development of biomarkers that can predict the response of individual patients.

/pdf/biomarkers-for-clinical-benefit-of-immune-checkpoint-5arvhrqtht.pdf

Biomarkers for Clinical Benefit of Immune Checkpoint Inhibitor Treatment-A Review From the Melanoma Perspective and Beyond

Predictive biomarkers of response for immune checkpoint inhibitors in non-small-cell lung cancer.

Neutrophil-to-Lymphocyte ratio (NLR) and Platelet-to-Lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab

Response to immune checkpoint inhibitors depends on tumor intrinsic properties and also on host factors in the tumour microenvironment including the presence of immune cells (IC) We hypothesized that nivolumab efficacy varies across different metastatic sites We retrospectively analyzed computed tomography scans of patients with metastatic non-small cell lung carcinoma (NSCLC) receiving nivolumab RECIST 11 criteria were applied to assess the overall response rate (ORR) and organ-specific response rate (OSRR) We analyzed 52 patients including 44% females, 58% adenocarcinoma and 8% never smokers Involved organs had target-lesions in the lung (42%), liver (25%), lymph nodes (56%) and soft tissue (13%) and non-target lesions in the bones (23%) ORR and disease control rate (DCR) were 20% and 45%, respectively Median overall survival, progression-free survival and duration of response were 119, 23 and 103 months OSRR and organ-specific DCR (OSDCR) were 28% and 90% in lymph nodes, 8% and 54 in the liver, and 9% and 55% in lung metastases Nine out of 12 patients with bone metastases had progressive lesions The cumulative incidence probability of organ-specific progression at 6 months was 14% in lymph nodes, 42% in the liver, 36% in lung metastases and 26% in the primary tumor, 29% in soft tissue and 33% in adrenal metastases In conclusion, the efficacy of immunotherapy is dependent on the metastatic location Treatment appears more active in lymph nodes compared to other organ sites such as liver, adrenals and bone Future strategies may include additional local treatment in case of oligoprogression in these organs in patients with otherwise sustained treatment benefit

Mirjam Krapf

Papers

Neutrophil-to-Lymphocyte ratio (NLR) and Platelet-to-Lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab

Organ-specific response to nivolumab in patients with non-small cell lung cancer (NSCLC).