Composition, Spatial Characteristics, and Prognostic Significance of Myeloid Cell Infiltration in Pancreatic Cancer

Abstract

Purpose. While abundant myeloid cell populations in the pancreatic ductal adenocarcinoma (PDAC) microenvironment have been postulated to suppress anti-tumor immunity, the composition of these populations, their spatial locations, and how they relate to patient outcomes are poorly understood. Experimental Design. To generate spatially-resolved tumor and immune cell data at single cell resolution, we developed two quantitative multiplex immunofluorescence assays to interrogate myeloid cells (CD15, CD14, ARG1, CD33, HLA-DR) and macrophages [CD68, CD163, CD86, interferon regulatory factor 5 (IRF5), MRC1 (CD206)] in the PDAC tumor microenvironment. Spatial point pattern analyses were conducted to assess the degree of co-localization between tumor cells and immune cells. Multivariable-adjusted Cox proportional hazards regression was used to assess associations with patient outcomes. Results. In a multi-institutional cohort of 305 primary PDAC resection specimens, myeloid cells were abundant, enriched within stromal regions, highly heterogeneous across tumors, and differed by somatic genotype. High densities of CD15 + ARG1 + immunosuppressive granulocytic cells and M2-polarized macrophages were associated with worse patient survival. Moreover, beyond cell density, closer proximity of M2-polarized macrophages to tumor cells was strongly associated with disease-free survival, revealing the clinical significance and biologic importance of immune cell localization within tumor areas. Conclusions. A diverse set of myeloid cells are present within the PDAC tumor microenvironment and are distributed heterogeneously across patient tumors. Not only the densities but also the spatial locations of myeloid immune cells are associated with patient Research.

Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

“…Moreover, features of the TME play key roles in regulating sensitivity to chemotherapy, radiotherapy and immunotherapy [ 99 , 100 ]. The balance and geography of myeloid and lymphoid elements in the TME is a critical element which associates with clinical outcomes [ 101 , 102 ]. For example, a high ratio of CD8 T cells to CD68 + macrophages is associated with prolonged OS, while increased myeloid cell infiltration or close proximity of macrophages and tumor cells is associated with poor OS [ 101 , 102 ].…”

“…The balance and geography of myeloid and lymphoid elements in the TME is a critical element which associates with clinical outcomes [ 101 , 102 ]. For example, a high ratio of CD8 T cells to CD68 + macrophages is associated with prolonged OS, while increased myeloid cell infiltration or close proximity of macrophages and tumor cells is associated with poor OS [ 101 , 102 ]. Consistent with the concept of immune infiltrates in the TME modulating sensitivity to platinum chemotherapy/PARPi, in unselected patients with breast cancer, robust pre-treatment T cell infiltration is associated with improved response to olaparib [ 103 ].…”

Systemic Delivery of Oncolytic Adenovirus to Tumors Using Tumor-Infiltrating Lymphocytes as Carriers

“…Other cell types other than TILs, may have also influenced the tumor volumes at early time points, particularly myeloid cells. In humans, myeloid cells are a large component of the tumor microenvironment of pancreatic cancer [ 36 ]. Assuming that hamster HapT1 tumors have similar composition, any impact on such population utilizing TILs and TILT-123 could ultimately reflect on tumor volume.…”

Challenges and Opportunities in the Statistical Analysis of Multiplex Immunofluorescence Data

“…Another benefit of mIF platforms that they can detect both the abundance and spatial location within the tissue sample of multiple cell types. The use of mIF has been recently applied to study the spatial proximity between T and PD-L1 expressing cells in oropharyngeal squamous cell carcinoma [ 38 ], the spatial heterogeneity of macrophages in gastric cancer [ 39 ], and the spatial composition of myeloid cells in pancreatic cancer [ 40 ].…”