Characterization of Immunosuppressive Myeloid Cells in Merkel Cell Carcinoma: Correlation with Resistance to PD-1 Pathway Blockade.

PURPOSE: Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer. Although essentially all MCCs are antigenic through viral antigens or high tumor mutation burden, MCC has a response rate of only approximately 50% to PD-(L)1 blockade suggesting barriers to T-cell responses. Prior studies of MCC immunobiology have focused on CD8 T-cell infiltration and their exhaustion status, while the role of innate immunity, particularly myeloid cells, in MCC remains underexplored. EXPERIMENTAL DESIGN: We utilized single-cell transcriptomics from 9 patients with MCC and multiplex IHC staining of 54 patients' preimmunotherapy tumors, to identify myeloid cells and evaluate association with immunotherapy response. RESULTS: Single-cell transcriptomics identified tumor-associated macrophages (TAM) as the dominant myeloid component within MCC tumors. These TAMs express an immunosuppressive gene signature characteristic of monocytic myeloid-derived suppressor cells and importantly express several targetable immune checkpoint molecules, including PD-L1 and LILRB receptors, that are not present on tumor cells. Analysis of 54 preimmunotherapy tumor samples showed that a subset of TAMs (CD163+, CD14+, S100A8+) selectively infiltrated tumors that had significant CD8 T cells. Indeed, higher TAM prevalence was associated with resistance to PD-1 blockade. While spatial interactions between TAMs and CD8 T cells were not associated with response, myeloid transcriptomic data showed evidence for cytokine signaling and expression of LILRB receptors, suggesting potential immunosuppressive mechanisms. CONCLUSIONS: This study further characterizes TAMs in MCC tumors and provides insights into their possible immunosuppressive mechanism. TAMs may reduce the likelihood of treatment response in MCC by counteracting the benefit of CD8 T-cell infiltration. See related commentary by Silk and Davar, p. 1076.

Impact of smoking on postoperative complications after anterior cervical discectomy and fusion.

The relationship between smoking and the risk of postoperative complications among anterior cervical discectomy and fusion (ACDF) patients remains uncertain. We compared the postoperative complication rates following ACDF surgery among non-smokers, current smokers, and ever-smokers. Baseline and outcome data were obtained from the 2005- to 2014 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database for patients over the age of 18 who underwent non-emergent ACDF surgery. Information on current smoking and ever-smoking status was extracted. Outcomes included development of at least one complication, development of a major complication, in-hospital mortality, and length of stay. ACDF patients were either current smokers (7847, 30.3%) or not current smokers (18,022, 69.7%); 33.0% of all patients (n=8542) had ever smoked. Current smoking status was not associated with increased odds of any one complication (P=0.584) or any major complication (P=0.138). In addition, using the number of pack-years as the primary independent variable, multivariate logistic regression analysis revealed that the number of pack-years was not significantly associated with greater odds of developing any one complication (P=0.276) or any major complication (P=0.334). However, ever-smoker status did present significantly higher odds of any major complication (OR, 1.333; 95% CI 1.007-1.764; P=0.044) than for non-smokers. These results suggest that any patient with a prior smoking history should be considered a higher risk surgical candidate when attempting ACDF.