Identification of Functional Heterogeneity of Carcinoma-Associated Fibroblasts with Distinct IL6-Mediated Therapy Resistance in Pancreatic Cancer

Abstract

The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of fibroblasts as part of the host response to cancer. Employing single-cell RNA-sequencing, multiplex immunostaining, and several genetic mouse models, we identify carcinoma-associated fibroblasts (CAFs) with opposing functions in PDAC progression. Depletion of fibroblast activation protein (FAP)+ CAFs results in increased survival, in contrast to depletion of alpha smooth muscle actin (aSMA)+ CAFs that leads to decreased survival. Tumor-promoting FAP+ CAFs (TP-CAFs) and tumor-restraining aSMA+ CAFs (TR-CAFs) differentially regulate cancer-associated pathways and accumulation of Tregs. Improved efficacy of gemcitabine is observed when IL-6 is deleted from aSMA+ CAFs but not from FAP+ CAFs employing dual-recombinase genetic PDAC models. Improved gemcitabine efficacy due to lack of IL-6 synergizes with anti-PD1 immunotherapy to significantly improve survival of PDAC mice. Our study identifies functional heterogeneity of CAFs in PDAC progression and their different roles in therapy response.

The Desmoplastic Stroma of Pancreatic Cancer: Multilayered Levels of Heterogeneity, Clinical Significance, and Therapeutic Opportunities

“…In murine PDAC models, ACTA2 deletion has developed an undifferentiated tumor and promoted tumor progression [169]. Depleting FAP-expressing CAFs results in the prolonged survival of murine PDAC models, whereas the depletion of ACTA2-expressing CAFs leads to shortened survival [170]. Moreover, this study has shown improved gemcitabine efficacy as well as synergy with the PDCD1 pathway blockade when IL6 is selectively ablated in ACTA2expressing CAFs [170].…”

“…Depleting FAP-expressing CAFs results in the prolonged survival of murine PDAC models, whereas the depletion of ACTA2-expressing CAFs leads to shortened survival [170]. Moreover, this study has shown improved gemcitabine efficacy as well as synergy with the PDCD1 pathway blockade when IL6 is selectively ablated in ACTA2expressing CAFs [170]. Tumor-promoting CAFs and tumor-restricting CAFs are likely mixed, even in a single clinical tumor, and this balance within a PDAC could be modified by several CAF-targeted approaches (i.e., Hedgehog inhibitors and anti-FAP agents), which may lead to altered clinical outcomes.…”

Good and Bad Stroma in Pancreatic Cancer: Relevance of Functional States of Cancer-Associated Fibroblasts

“…Again, this observation seems to contradict the prevailing notion that CAFs generally contribute to tumor resistance to ICIs [ 54 , 55 ]. A recent study showed that IL-6 production from α-SMA + myCAFs, but not pCAFs, marked by the expression of fibroblast activation protein-α (FAP-α), contributes to the resistance of pancreatic cancer to chemotherapy and ICIs ( Figure 2 ) [ 56 ]. Thus, the rCAF and pCAF balance seems to be important for regulating antitumor immunity and sensitivity to ICIs, although currently no ICIs have been shown to be effective in the treatment of human PDAC.…”

Crosstalk between Pancreatic Cancer Cells and Cancer-Associated Fibroblasts in the Tumor Microenvironment Mediated by Exosomal MicroRNAs

“…CAFs with high expression of α-SMA were named myCAFs, whereas CAFs with low α-SMA levels that secrete inflammatory cytokines such as IL-6 and leukemia inhibitory factor (LIF) were defined as iCAF [ 24 ]. McAndrews et al [ 25 ] found that depletion of FAP+ CAFs resulted in a survival benefit, while depletion of α-SMA+ CAFs caused increased mortality in mouse models of PDAC. The oncogenic FAP+ CAFs and anti-tumor α-SMA+ CAFs were proved to regulate cancer-related pathways and regulatory T cells via different mechanisms.…”