Background: Circulating stromal cells, ie Cancer Associated Macrophage-Like cells (CAMLs), are prevalent in the circulation of non-small cell lung carcinoma (NSCLC) patients (pts), appearing as giant phagocytic macrophages that represent an inflammatory pro-tumorigenic microenvironment. Previously it was shown that pts with engorged CAMLs of ≥50µm after treatment are prognostic for poor clinical outcomes. However, analyzing the dynamic changes in CAMLs over time or in response to treatment, ie chemoradiation (CRT) and immunotherapy (IMT) has not been evaluated. We monitored n = 182 unresectable NSCLC stage II/III pts treated with CRT alone (n = 91) or with concurrent IMT (n = 91) to evaluate changes in CAMLs before and after CRT induction at it relates to progression free survival (PFS) or overall survival (OS). Methods: We prospectively procured pts from 3 different regimes, treated with CRT alone (n = 91), treated concurrently with CRT & Atezolizumab (n = 40, clinical trial NCT02525757), or treated concurrently with Durvalumab (n = 51). We recruited 182 pts with pathologically confirmed stage II/III unresectable NSCLC. A total of 15 mL blood samples were drawn prior to start of therapy at baseline (BL) and ̃5 weeks (T1) after CRT induction. Blood filtration was done using CellSieve filters, then CAMLs were identified and measured to evaluate PFS & OS hazard ratios (HRs) by censored univariate and multivariate analyses at 2 years. Results: CAMLs were found in 89% of all samples tested. Increases in CAML size between BL & T1 were significantly correlated with worse clinical outcomes, with higher CAML increases correlated with increasingly worse outcomes, including CAML increases >10μm resulting in PFS HR=1.7 p = 0.027 & OS HR=1.9 p = 0.045, through increases >40μm resulting in PFS HR=2.1 p = 0.013 & OS HR=2.5 p = 0.020. Increases of CAMLs >35μm was optimal at stratifying pts PFS HR=2.2 p = 0.005 & OS HR=2.8 p = 0.005. Specifically, pts treated with only CRT and increasing CAMLs >35μmhad significantly worse PFS HR=2.7 p = 0.029 & OS HR=4.1 p = 0.013. In parallel, pts treated with CRT+IMT and increasing CAMLs >35μm had near significance for worse PFS (HR=2.1 p = 0.073) & OS (HR=2.3, p = 0.147), though follow up clinical data is ongoing. Conclusions: Our data suggest that in unresectable stage II/III NSCLC, tracking the increase of pro inflammatory immune cells (CAMLs) in circulation during therapy induction can identify pts less responsive to CRT or PD-L1/PD-1 IMTs.