204P - Deciphering the crosstalk between tumor and circulating immune microenvironment in advanced NSCLC patients undergoing immunotherapy

Background

Exploring the interaction between tissue and circulating immune descriptors may represent a critical step in our understanding of cancer immunity cycle to dissect distinct immunotherapy (IO) outcomes. Thus, we determined whether a comprehensive immune profiling, including tumor immune microenviroment (TIME) and peripheral blood (PB) might offer an “holistic” view of patient-specific immune background, potentially leading to new personalized therapeutic strategies.

Methods

On 59 consecutive IO-treated NSCLC patients, digital microscopy was employed on tissue samples to assess densities and spatial distribution (intratumor and stromal) of different Tumor-infiltrating lymphocytes (TILs) subpopulations (CD3+, CD4+-CD8+, PD-1+); peripheral blood (PB) samples were analyzed by Flow cytometry and immunenzymatic assay to determine circulating immune-inflammatory features. Statistical analyses were conducted to assess potential correlations between TIME and blood immune features.

Results

In our cohort of NSCLC patients, PB analysis revealed a significant direct correlation between the density of total and intratumor CD3+ TILs and the percentage of circulating CD3+ T cells. Moreover, higher CD8+ TILs correlated with an increase in circulating CD8+Ki67+ and a decrease in immunosuppressive Tregs (P<0.05). Cytokine analysis showed that IL-6 direclty correlated with TILs density, while IL-1β, IL-12p70, and IL-2 were linked to CD8/CD3 ratios (P<0.05). An inverse relationship was observed between PD-1/CD8 ratio and IL-1β, IFN-γ and TGF-β1, along with a negative correlation between IL-4 and PD-1+ TILs (P<0.05). Additionally, we found that PD-L1^neg patients displayed higher levels of blood monocytes and Tregs. Increased PD-L1 expression correlated with higher CD3+ TILs, and a significant inverse relationship was noted between PD-L1 levels and the PD1-to-CD8 TILs ratio, suggesting that PD-L1+ cancer cells may inhibit cytotoxic T cells.

Conclusions

Our findings strongly suggest the existence of a complex crosstalk between tissue and circulating compartments in shaping the immune response against the tumor and likely the proneness to benefit from immunotherapy in advanced NSCLC patients.

Legal entity responsible for the study

University Hospital of Parma.

Funding

AIRC Associazione Italiana Ricerca sul Cancro.

Disclosure

All authors have declared no conflicts of interest.