Abstract A052: Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to immune checkpoint blockade therapy
Authors: Iida Tadashi , Takayuki Owaki , Uetsuki Kota , Kentaro Yamao , Mizutani Yasuyuki , Ishikawa Takuya , Enomoto Atsushi , Kawashima Hiroki 
Published: January 2024

Background/Purpose: Cancer-associated fibroblasts (CAFs) are one of the major cell subsets in the tumor microenvironment. Their proliferation is observed in almost all invasive cancers but is most prominent in aggressive cancers with marked desmoplastic stromal reactions, such as pancreatic ductal adenocarcinoma (PDAC). Recent single-cell transcriptomic analyses have revealed CAF heterogeneity. One approach to classify CAFs is based on their cellular roles in cancer progression: cancer-promoting CAFs (pCAFs) and cancer-restraining CAFs (rCAFs). We previously identified the glycosylphosphatidylinositol-anchored protein Meflin as a rCAF-specific marker and showed that Meflin-positive CAFs are converted into Meflin-negative CAFs during cancer progression by cell lineage experiments. Interestingly, another previous study demonstrated that the number of Meflin+ rCAFs positively correlated with the response to immune checkpoint blockade (ICB) therapy in patients with non-small cell lung cancer (NSCLC). This was also shown in mouse models, where tumors developed in Meflin KO mice and mice that overexpress Meflin showed lower and higher sensitivity to anti-PD1 antibody treatment, respectively. These data suggest the significance of the balance between pCAFs and rCAFs in ICB therapy, being consistent with recent studies that have shown the critical role of CAFs in anti-tumor immunity So, The aim of this study is to establish the effects of strategies to increase the number of rCAFs on the sensitivity to ICB therapy in PDAC. Material/Methods: A search for chemical compounds that upregulate Meflin expression was performed. We then investigated the effect of the compound on the efficacy of anti-PD-L1 antibody treatment using mouse murine models of PDAC. We also addressed the mechanism by which Meflin+ rCAFs shape the immune tumor microenvironment that potentiates the efficacy of ICB therapy. Results: We performed a chemical library screen for compounds that convert protumor CAFs into rCAFs by inducing Meflin expression. As a result, they identified the synthetic retinoid AM80 as a candidate drug that achieves that CAF conversion. Next, we observed that the induction of a Meflin-positive CAF subset with a cancer-suppressive role through the oral administration of Am80 improves intratumoral delivery and efficacy of anti-PD-L1 antibody treatment in pancreatic cancer models. Interestingly, Am80 exerted this effect when administered to tumors prior to, but not concomitant with, anti-PD-L1 antibody in wild-type but not Meflin-deficient mice. Meflin+ rCAFs induced polarization of macrophages to the M1-like phenotype and durable anti-PD-L1 treatment-mediated anti-tumor responses. Conclusion: Our data suggest that strategy of pharmacologic conversion of CAF from protumor phenotype to an antitumor phenotype CAF can improves the sensitivity of pancreatic cancer to ICB therapy.

Citation Format: Tadashi Iida, Owaki Takayuki, Kota Uetsuki, Yamao Kentaro, Yasuyuki Mizutani, Takuya Ishikawa, Atsushi Enomoto, Hiroki Kawashima. Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to immune checkpoint blockade therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A052.