Myeloid Derived Suppressor Cells (MDSCs), Heme-oxygenase-1 (HO-1) and C88 expression in circulating monocytes: a study of impact on outcome in advanced cancer patients treated with Immune checkpoint inhibitors (ICIs).

The long-term remissions induced by immune-checkpoint inhibitors (ICIs) in many types of cancers haveopened the possibility of a broader use of immunotherapy. Although the advantage of ICIs resides in itscapacity to achieve long-term, even complete responses, the reality is that majority of patients do notbenefit from these treatments. Despite a huge step forward, ICI has not resolved the issue of cancertreatment. With immune-checkpoint immunotherapy, a door has been opened, but the case is not closed.Our hopes for the next decade are that biomarker for predicting ICI efficacy and toxicity will be identifiedtogether with clinical parameters to optimize ICI regimens and new combinations. During this PhD term myaim was to draw attention to the impact of HO-1 in circulating monocytes, presence of myeloid derivedsuppressor cells and complement receptor C5aR1 on monocyte subpopulation on advanced cancer patientsenrolled for ICI therapy.Aberrant immune cells have been detected in tumor microenvironment; in particular, tumor associatedmacrophages (TAMs), with high levels of hemeoxigenase-1 (HO-1 + ) seem to play a crucial defensemechanism through antioxidant, anti-inflammatory and anti-apoptotic properties. With these premises, weevaluated the prognostic role of HEME catabolism by the assessment of HO-1 expression level inmonocytes subpopulations in peripheral blood samples of oncological patients, candidates to ICIs, toindividuate a new target and prognostic blood marker. By now we enrolled in this study 126 patients withadvanced Lung Cancer (L; n=89), Head and Neck Cancer (HNC, n=14), Melanoma (M; n=13) and Renal CellCarcinoma (RCC; n=10). Peripheral Blood Mononuclear Cells (PBMCs) were collected at baseline andexpression of Heme-oxigenase-1 (HO-1) in terms of Median Fluorescence Intensity (MFI) was assessed byFlow Cytometry, in three monocyte subsets: classical (CD14+/CD16-), non-classical (CD14-/CD16+) andintermediate (CD14+/CD16+). Numerous clinical studies have demonstrated that high levels of MDSCs arepositively correlated with poor prognosis in patients with cancer owing to their immunosuppressivefunctions. For these reasons, we phenotyped Myeloid-derived suppressor cells (MDSCs) in peripheral bloodsamples of these patients and associated their levels with the clinical outcomes in advanced cancer patientstreated with ICI’S. Existing and accumulating new evidence suggest that the complement system plays amajor role in the regulation of TME. Cancer cells along with the optimization of complement-mediatedfunctions remodel the TME and facilitate the tumor progression, metastasis, and evasion of the immunesystem with this premise we aimed to evaluate expression levels of C5aR1 (CD88) on monocyte subset andassociate it as a potential baseline biomarker for therapeutic outcomes. In Major Results: Wedemonstrated.1) A higher proportion of non-classical monocyte subset in HNC, M and RCC, instead in LCthis trend was not observed.2) In all studied cancers the levels of HO-1 were significantly higher in classical monocytes,HO-1 levels were analyzed for their prognostic and predictive potential of clinical outcome.3) C5aR1 (CD88) on monocyte subset were also studied and its levels and role in clinicaloutcomes in advanced cancer patients was reported.4) We also phenotyped and identified Myeloid derived suppressor cells (MDSCs) anddemonstrated that levels MDSCs are associated with therapy outcomes in some advancedcancer treated with ICIs.5) Apart from this the prognostic and predictive potential was analyzed for advanced cancerpatients treated with ICIs based on several clinical biomarkers including baseline clinicalcharacteristics of patients. Additionally, nine blood based clinical biomarkers wereidentified and their prognostic potential is analyzed.