Abstract
ObjectivesSelective targeting of cancer-associated fibroblasts (CAFs) has been proposed to synergize with immune-checkpoint inhibitors. While the roles of CAFs in cancer development are well described, their immune-regulatory properties remain incompletely understood. This study investigates correlations between CAF and immune-markers in tumor stroma from non-small cell lung cancer (NSCLC) patients, and examines whether a combination of CAF and immune cell scores impact patient prognosis.MethodsTumor specimens from 536 primary operable stage I-III NSCLC patients were organized in tissue microarrays. Expression of protein-markers was evaluated by immunohistochemistry.ResultsFibroblast and stromal markers PDGFRα, PDGFRβ, FAP-1 and vimentin showed weak correlations while αSMA, and Masson’s trichrome did not correlate with any of the investigated markers. Hierarchical clustering indicated the existence of different CAF-subsets. No relevant correlations were found between any CAF-marker and the immune-markers CD3, CD4, CD8, CD20, CD68, CD1a, CD56, FoxP3 and CD45RO. High density of fibroblast-activation protein positive mesenchymal cells (CAFFAP) was associated with better prognosis in tumors with high infiltration of CD8 and CD3 T-lymphocytes.ConclusionsThe presented data suggest that CAFs, irrespective of identity, have low influence on the degree of tumor infiltration by inflammatory- and/or immune-cells. However, CAFFAP may exert immuno-adjuvant roles in NSCLC, and targeting CAFs should be cautiously considered.
Highlights
In solid tumors, complex and reciprocal interactions between neoplastic cells and surrounding cells lead to a tumor tissue compartment often referred to as reactive stroma, desmoplastic stroma or tumor microenvironment
No relevant correlations were found between any Cancer-associated fibroblasts (CAFs)-marker and the immune-markers CD3, CD4, cluster of differentiation 8 (CD8), CD20, CD68, CD1a, CD56, FoxP3 and CD45RO
We have previously explored the prognostic significance of CAF-markers in the stroma of resected non-small cell lung cancer (NSCLC) tumors [8], with the intriguing finding that high CAFFAP levels were associated with an improved prognosis in patients with squamous cell carcinoma
Summary
Complex and reciprocal interactions between neoplastic cells and surrounding cells lead to a tumor tissue compartment often referred to as reactive stroma, desmoplastic stroma or tumor microenvironment. Fibroblasts associated with tumors normally display an activated phenotype, and depending on their origin, morphology or spatial distribution, they may receive different names such as myofibroblasts, activated tumor fibroblasts, activated stellate cells, bone marrow-derived mesenchymal stromal cells or pericytes [4, 5]. Several markers such as αSMA, FAP-1, desmin, podoplanin, neuron-glial antigen 2 (NG2) and PDGF receptors-α and -β are used to identify CAFs. due to the great plasticity of this cell population, none of these markers can be used as a universal marker for all CAFs as their expression is likely to be temporal and context dependent [6]. These markers have demonstrated unfavorable outcomes related to survival (Table 1)
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