Abstract
BackgroundA dual blockade against the novel immune checkpoint inhibitor lymphocyte activation gene-3 (LAG-3) and programmed cell death protein-1 (PD-1) is currently considered in advanced breast cancer. Nevertheless, PD-1 or LAG-3 expression within distant metastatic breast cancer tissue remains understudied.MethodsTo address this knowledge gap, we investigated the PD-1 and LAG-3 expression in combination with the CD8-based immune phenotype in intrapatient matched primary tumor distant metastases, representing 95 breast cancer patients with metastases occurring at four different anatomical locations. The immune phenotype was categorized into 2 categories: inflamed corresponding to the clinical category “hot” and exhausted or desert consistent with clinically “cold” tumors.ResultsMetastases of “cold” primary tumors always remained “cold” at their matched metastatic site. Expression of PD-1/LAG-3 was associated with a “hot” immune phenotype in both the primary tumors and metastases. We could not observe any association between the immune phenotype and the breast cancer molecular subtype. Brain and soft tissue metastases were more commonly inflamed with signs of exhaustion than other anatomical sites of metastases. Taken together, (i) the immune phenotype varied between sites of distant metastases, and (ii) PD-1+/LAG-3+ was strongly associated with a “hot” immune phenotype and (iii) was most prevalent in brain and soft tissue metastases among distant metastases.ConclusionsOur data strongly support an integrated analysis of the immune phenotype together with the PD-1/LAG-3 expression in distant metastases to identify patients with inflamed but exhausted tumors. This may eventually improve the stratification and likelihood for advanced breast cancer patients to profit from immunotherapy.
Highlights
Immunotherapy with immune checkpoint inhibitors is usually considered in advanced metastatic breast cancer
To translate the frequency and spatial distribution of CD8+ T cells within the tumor compartments to a certain immune phenotype, we first semiquantitatively evaluated CD8+ T cells within Primary breast tumor (PBT) and Distant metastasis (MET) (Fig. 1b) to categorize them into three immune phenotypes corresponding to the clinical categories “hot” and “cold” (Fig. 1c)
As published previously [17], we evaluated the intratumoral compartment of the “tumor center” [22] compartment based on the notion that a direct contact between CD8+ T cells and tumor cells must occur for CD8+ T cell-mediated cytotoxicity
Summary
Immunotherapy with immune checkpoint inhibitors is usually considered in advanced metastatic breast cancer. Monotherapy against programmed cell death protein-1 (PD-1) showed only the modest tumor and durable response rates in breast cancer (4–25%) [2]. In the need of novel strategies, in vivo studies provided convincing evidence that a dual blockade against PD-1 and the novel immune checkpoint receptor lymphocyte-associated gene-3 (LAG-3) [3] can result in tumor reduction and increase of survival [4, 5] by restoring CD8+ T cell function [6]. Highly immunogenic tumors susceptible to immunotherapy like melanoma, microsatellite instable colorectal cancer, or triple-negative breast cancer carry PD-1+/LAG-3+ CD8+ tumor-infiltrating T cells [8]. A dual blockade against the novel immune checkpoint inhibitor lymphocyte activation gene-3 (LAG3) and programmed cell death protein-1 (PD-1) is currently considered in advanced breast cancer. PD1 or LAG-3 expression within distant metastatic breast cancer tissue remains understudied
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