Purpose: PD-1/PD-L1 axis inhibitors have been proven effective, especially in patients with tumors expressing Programmed Death Ligand 1 (PD-L1). Their clinical efficacy in patients with epidermal growth factor receptor (EGFR) activating mutations is still unclear, while KRAS mutations seem to be associated with good response. Experimental Design: We used multiplexed quantitative immunofluorescence (QIF) to investigate PD-L1 expression and to characterize Tumor Infiltrating Lymphocyte (TIL) populations and their activation status in over 150 Non-Small Cell Lung Cancer (NSCLC) patients with known mutation status. Results: PD-L1 expression was significantly lower in EGFR mutant compared to KRAS mutant and EGFR/KRAS Wild Type (WT) tumors. KRAS mutant tumors were more inflamed with higher CD4+, CD8+ and CD20+ TILs. Subgroup analysis by TILs activation status revealed that EGFR mutants had a high frequency of inactive TILs even though lymphocytes were present in the tumor microenvironment. In contrast, in KRAS mutants, when TILs were present, they were almost always active. Additionally, we found differences between EGFR mutation sites in CD8+ expression and TILs activation profile. Finally, activated EGFR correlated with increased PD-L1 expression in EGFR mutants but not in EGFR WT, while TIL activation was associated with higher PD-L1 only in EGFR/KRAS WT. Conclusions: Our findings demonstrate the unique immune profile of EGFR mutant tumors. The high frequency of inactive TILs could explain the low immunotherapy response rates in these patients, while PD-L1 as a predictive biomarker may reflect the constitutive oncogenic signaling rather than immune signaling, which would be associated with high PD-L1 levels and TILs activation.
Thrombodynamics is a promising method for measuring coagulation by imitation of in vivo conditions, and is being used in basic research. More work and correlative clinical investigations are still required to determine whether this method will be clinically useful in the future.
9076 Background: PD-1/PD-L1 axis inhibitors have been proven effective, especially in patients expressing Programmed Death Ligand 1 (PD-L1). Their clinical efficacy in patients with epidermal growth factor receptor (EGFR) activating mutations is still unclear, while KRAS mutations seem to be associated with high response rates. In this study we investigated the expression of PD-L1, PD-L2 and Tumor Infiltrating Lymphocyte (TIL) status as a function of mutation status in Non-Small Cell Lung Cancer (NSCLC). Methods: We used the AQUA method of quantitative fluorescence (QIF) to compare PD-L1 and PD-L2 expression and to characterize TILs populations and their activation status in over 150 NSCLC patient tumors with known mutation status. EGFR activation was assessed in situ using the proximity ligation assay (PLA) for EGFR and GRB2 and T cell activation was assessed using a novel multiplexed QIF assay including CD3, Granzyme B and Ki67. Results: PD-L1 tumor and stroma expression was significantly lower in EGFR mutant compared to KRAS mutant (p = 0.009) and EGFR/KRAS Wild Type (p < 0.0001) tumors, while they had a higher frequency of PD-L2 expression. Conversely, KRAS mutants had significantly lower PD-L2 tumor and stroma expression but they were also more inflamed with higher CD4+, CD8+ and CD20+ TILs. Subgroup analysis of patients by their TILs activation status revealed that EGFR mutants had a very high frequency of inactive TILs even though lymphocytes were present in the tumor microenvironment. In contrast, in KRAS mutants, when TILs were present, they were almost always active. Finally, we find that PLA-defined activated EGFR correlated with increased PD-L1 expression in EGFR mutants but not in EGFR WT, while TIL activation was associated with higher PD-L1 in EGFR/KRAS WT. Conclusions: Our findings are consistent with the unique biology of EGFR mutant tumors. The high frequency of inactive TILs could explain the low immune therapy response rates in this patient group. Similarly, in this group, the reason PD-L1 expression fails to predict response may be due to expression as a result of constitutive oncogenic signaling rather than immune signaling, which would be associated with high PD-L1 levels and TILs activation.
BackgroundMerkel cell carcinoma is a rare and aggressive skin malignancy that arises from primary neural cells and has a tendency for local recurrence and regional lymph node metastases. There are only a few cases in the literature reporting metastases of Merkel cell carcinoma to the gastrointestinal tract.Case presentationWe present a 70 year old Caucasian female with distant history of Merkel cell carcinoma who presented with iron-deficiency anemia. Colonoscopy performed later for the evaluation of anemia revealed 1 cm polyp in ascending colon which turned out to be the recurrence of Merkel cell carcinoma.ConclusionMetastatic Merkel cell carcinoma to the gastrointestinal tract or any other organ should be considered in patients with a history of Merkel cell carcinoma.
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