Tumor associated CD90+ mesenchymal cells are chemoresistant and immunosuppressive in human non-small cell lung cancer

Background:

The majority of advanced NSCLC patients fail to respond to inhibitors targeting the immune-checkpoint programmed death-1 (PD-1) pathway suggesting additional immunosuppressive barriers exist in the tumor microenvironment (TME) such as the non-tumor stroma. Here we isolated and characterized novel CD90-expressing tumor pericytes together with tumor infiltrating lymphocytes (TILs) to characterize their function.

Material and method:

We used flow cytometry to profile the non-tumor stroma to investigate the link between high-level cellular profiling data and clinical variables in resectable NSCLC.

Result:

We profiled both lung adenocarcinoma (AC, n = 69) and squamous cell carcinoma (SQCC, n = 66) patient samples and found an enrichment in non-tumor CD90⁺ mesenchymal cells. Besides tumor epithelium (EpCAM+), CD90⁺ mesenchymal cells upregulate PD-L1, which was confirmed histologically. Spatially, CD90⁺ mesenchymal cells lined blood vessels invading tumor islands, and also were located in the stroma colocalizing with CD73 in both AC and SQCC. CD90⁺ mesenchymal prospectively isolated from both AC and SQCC were resistant to the damaging effects of chemotherapy, while priming with INFα and IFNγ induced the upregulation of PD-L1, indoleamine 2,3-dioxygenase (IDO) and secretion of key cytokines/chemokines involved in the functional modification of leukocytes. In these same patient samples, we found that tumor infiltrating CD8⁺ and CD4⁺ T cells (TILs) in both AC and SQCC were contained primarily in the memory compartment with an altered differentiation state. Importantly, we were able to identify a combination of compositional features that were predictive of tumor recurrence and survival such as high levels of memory CD4⁺PD-1⁺ TILs. Despite expressing several markers of exhaustion such as PD-1, TIM3 and downregulation CD127, CD4⁺ and CD8⁺ effector memory TIL subsets maintain an ability to proliferate in culture; however, their function was suppressed in the presence of immune primed CD90⁺ cells.

Conclusion:

Our observations suggest that pharmacological modulation of independent biological features present in the non-tumor stroma such as CD90+ mesenchymal cells and their immunosuppressive secretome may be necessary to improve host anti-tumor immunity and patient outcomes in NSCLC.