Distribution and prognostic relevance of tumor-infiltrating lymphocytes (TILs) and PD-1/PD-L1 immune checkpoints in human brain metastases

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.

Anti‐PD‐L1 treatment enhances antitumor effect of everolimus in a mouse model of renal cell carcinoma

“…In human RCC, TILs themselves do not denote the efficacy of antitumor immunity, but tumor infiltrating CD8 + T cells bearing proliferative activity could reflect effective antitumor immunity . The cytotoxicity of CD8 + T cells against the tumor is influenced by immunosuppressive factors in the local tumor microenvironment, such as cytokines released from innate immune cells, Tregs and myeloid derived suppressor cells, and signaling through immune checkpoint molecules including PD‐1/PD‐L1 . In the present study, EVE‐induced PD‐L1 upregulation within tumors suggest that EVE might prevent effective anti‐tumor immunity.…”

Peritumoral cuffing by T‐cell tumor‐infiltrating lymphocytes distinguishes HPV‐related oropharyngeal squamous cell carcinoma from oral cavity squamous cell carcinoma

“…Work from other groups has also demonstrated that HPV‐positive HNSCC with stromal T‐cell lymphocytic infiltrate, but not intratumoral T cells, is predictive of patient survival . The presence of a predominantly peritumoral immune reaction has now also been described for pancreatic adenocarcinoma and metastatic tumors of the brain and associated with improved clinical outcome, indicating this is likely not an organ‐restricted phenomenon.…”

The potential prognostic and predictive roles of programmed cell death protein 1 expressed by tumor-infiltrating lymphocytes in solid tumors: a meta-analysis

“…The detailed methodologies used to detect PD-1 are summarized in Table 2. Furthermore, 2 cohorts of patients were reported by Harter et al [24] and Webb et al [25] , respectively. PD-1 by TILs was assessed and the survival curves were reported independently, so they have been statistically analyzed as 4 individual studies.…”