Three Distinct Stroma Types in Human Pancreatic Cancer Identified by Image Analysis of Fibroblast Subpopulations and Collagen-Letter.

Abstract

Ogawa and colleagues reported the presence of three distinct stromal subtypes in pancreatic ductal adenocarcinoma (PDAC), associated with alternative disease characteristics (1). These data are important as stromal heterogeneity defining PDAC subtypes supports developing anti-stromal therapy (1). Intriguingly, the authors report the presence of a fibroblast-activating protein (FAP)-dominant stroma (F-stroma), that compared with other stromal types was low in CD8 T cells and associated with poor survival. T-cell exclusion is well recognized as a disease progression-promoting factor and appears to be the dominant immune phenotype in PDAC (Fig. 1A). The authors suggest that F-stroma may contribute to T-cell exclusion but do not test this notion directly. Thus prompted, we performed a morphometric analysis of the spatial distribution of both T cells and FAP on 31 treatment-naïve resected PDACs. We found that T cells indeed were excluded from the tumor per se (Fig. 1A and B), while FAP expression did not show a specific centromarginal gradient in our analysis. Importantly, no association between local FAP expression and T-cell presence was found (Fig. 1C). The most straightforward interpretation of our results, in conjunction with those of Ogawa and colleagues, is that the appearance of F-stroma could be a manifestation of a T cell–excluding phenotype rather than a standalone driver of exclusion itself. In this sense, the relation with Hedgehog signaling, as also pointed out of Ogawa and colleagues is interesting, as it has been shown in experimental rodents that Hedgehog can both suppress immune responses through regulating CXCL12 expression, and concomitantly enlarge the size of specific stromal compartments (2). Furthermore, as discussed by Ogawa and colleagues, F-stroma may facilitate other stromal subsets, for example, tumor-associated macrophages that have been implemented in tumor evasion via multiple mechanisms (e.g., by direct cell–cell interaction and/or secretion of stroma-modifying soluble factors) but obviously further work is necessary to substantiate these notions. The observation that T cells are generally excluded in PDAC (Fig. 1D) has major implications in the field and will direct research toward stromal factors. Counteracting T-cell exclusion with immune checkpoint inhibition by targeting PD-(L)1 might not be optimal as mainly inflamed cancer types (melanoma or microsatellite instability-high gastrointestinal cancers) benefit from this type of therapy, but unfortunately not PDAC (3, 4). The goal would certainly be to convert excluded (cold) tumors into inflamed (hot) tumors and subsequently consider combinations with treatments that further potentiates such T-cell responses (5). The key stromal target in PDAC, however, that will allow restoration of the tumor immunity cycle remains, unfortunately, obscure at best.See the Response, p. 427S.I. Buschow reports other support from ISA pharmaceuticals b.v. outside the submitted work. M.P. Peppelenbosch reports grants, personal fees, and non-financial support from Pfizer; grants and personal fees from ZONMW/NWO; and grants from KWF during the conduct of the study; grants from MLDS, CSC, and Wavax; personal fees from NCS, CSF, SNSF, ESF, and Dialecta; grants and personal fees from FWO and European Commission outside the submitted work. M.J. Bruno reports grants and other support from Boston Scientific, Cook Medical, Pentax Medical; grants from Mylan, ChiRoStim, and 3M outside the submitted work. No disclosures were reported by the other authors.