Abstract
The activation of immune cells by targeting checkpoint inhibitors showed promising results with increased patient survival in distinct primary cancers. Since only limited data exist for human brain metastases, we aimed at characterizing tumor infiltrating lymphocytes (TILs) and expression of immune checkpoints in the respective tumors. Two brain metastases cohorts, a mixed entity cohort (n = 252) and a breast carcinoma validation cohort (n = 96) were analyzed for CD3+, CD8+, FOXP3+, PD-1+ lymphocytes and PD-L1+ tumor cells by immunohistochemistry. Analyses for association with clinico-epidemiological and neuroradiological parameters such as patient survival or tumor size were performed. TILs infiltrated brain metastases in three different patterns (stromal, peritumoral, diffuse). While carcinomas often show a strong stromal infiltration, TILs in melanomas often diffusely infiltrate the tumors. Highest levels of CD3+ and CD8+ lymphocytes were seen in renal cell carcinomas (RCC) and strongest PD-1 levels on RCCs and melanomas. High amounts of TILs, high ratios of PD-1+/CD8+ cells and high levels of PD-L1 were negatively correlated with brain metastases size, indicating that in smaller brain metastases CD8+ immune response might get blocked. PD-L1 expression strongly correlated with TILs and FOXP3 expression. No significant association of patient survival with TILs was observed, while high levels of PD-L1 showed a strong trend towards better survival in melanoma brain metastases (Log-Rank p = 0.0537). In summary, melanomas and RCCs seem to be the most immunogenic entities. Differences in immunotherapeutic response between tumor entities regarding brain metastases might be attributable to this finding and need further investigation in larger patient cohorts.
Highlights
Interactions between immune and neoplastic cells play a major role during malignant progression nowadays being designated as the concept of cancer immunoediting [1]
The amount of CD8-positive lymphocytes was significantly higher in brain metastases of renal cell carcinoma (RCC) as compared to almost all other entities except melanomas and undifferentiated carcinomas, which were not otherwise specified (NOS) (Figure 2D)
We found the highest amount of PD-1positive lymphocytes in melanomas and
Summary
Interactions between immune and neoplastic cells play a major role during malignant progression nowadays being designated as the concept of cancer immunoediting [1]. One mechanism of tumor cells to escape from killing by immune cells is to interfere with immune checkpoints, thereby disabling an adequate immune response [2] Following this concept one promising target for an immune modulating therapy is the blocking of the Programmed cell death 1 (PD-1) / Programmed cell death ligand 1 (PD-L1) axis which is known to be crucial for immune escape mechanisms [3, 4]. PD-1 is expressed by activated lymphocytes and interactions of PD-1 with its ligand PD-L1, which is expressed by neoplastic cells [5, 6] lead to a reduction of T-lymphocyte activity in normal tissue, during inflammation, in cancer and decreases autoimmunity [5, 7, 8] These properties led to the development of therapies, blocking the PD-1/PD-L1 axis to intensify the anti-cancer immune response [9]. A limiting factor for efficacy may be poor infiltration of lymphocytes into the tumor tissue [13,14,15]
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