Abstract PR15: CD74 regulated inflammatory pattern is associated with TIL growth and favorable response to adoptive immunotherapy
Authors: Dai-Ogata  , Creasy Caitlin A. , Kim Sun-Hee , Roszik Jason , Hwu Patrick , Grimm Elizabeth A. , Bernatchez Chantale , Ekmekcioglu Suhendan 
Published: June 2022

Abstract
We previously reported that in Stage III melanoma patients’ tumors, positive expression of CD74 together with low or absent Macrophage Migration Inhibitory Factor (MIF) associates with favorable prognosis (Ekmekcioglu et al., CCR 2016). As both are known to be regulated by IFN-g, we suggest a differential IFN-g response as well as a novel role for CD74 that may be exploited to improve patient outcome. Our further analyses of The Cancer Genome Atlas (TCGA) datasets confirmed the role of CD74 in prognosis for patient survival, which is likely attributed to regulation of MHC-Class II and antigen presentation in the tumor microenvironment. Immune infiltration of T cells (TIL) into the melanoma microenvironment has been associated with improved survival for some patients, and also has been exploited to grow TIL in vitro for adoptive therapy. However, prognostic significance of immune infiltrating cells in melanoma and other tumors remains a relatively new concept, and markers related to suppressive versus active functional TIL remain unclear. From an ongoing clinical trial using TIL intended for adoptive immunotherapy, we have studied the melanoma patient tumor specimens (FFPE) from 20 patients whose autologous TIL lines grew to sufficient number for possible use clinically. We also examined another 20 sets of melanoma tumor from which the TIL did not grow or did not grow well. We analyzed the differences in the two groups of tumors (40 total FFPE) for CD74 regulated pathway features and inflammatory marker expression. CD74 regulated markers included CD44, MIF, and downstream inflammatory targets including inducible nitric oxide synthase (iNOS), nitrotyrosine (NT) and microsomal prostaglandin E synthase-1 (mPGES1). Our findings confirm our previous report in that tumor CD74 expression significantly associates with favorable OS and PFS (both, p=0.0038) and provides new data that in this set of patients the CD74 also correlates with best irRC of TIL treated patients. New findings include that the NT expression in tumor cells associated with poor TIL growth (p=0.014), as well as lack of clinical response to TIL treatment (p=0.02). We have also found that tumor cell-derived MIF and iNOS expression correlate with unfavorable prognosis for both OS and PFS (p=0.016 and 0.018, respectively). The iNOS and MIF coexpression characteristics and cellular distributions in the tumor are currently under way. In conclusion, we have identified the protein expression of CD74, MIF and of iNOS as providing survival information, and proposed that CD74+/MIF-/iNOS- together be considered to form a “signature” of good prognosis in general melanoma outcomes as well as TIL growth and favorable responses for these patients. Use of this signature for selecting patients for entry into TIL and possibly other immunotherapy trials, as well as research on the differential pathways of IFN-g signaling in melanoma, appear as important areas for future mechanistic research to improve patient outcome.
This abstract is also being presented as Poster B14.
Citation Format: Dai-Ogata, Caitlin A. Creasy, Sun-Hee Kim, Jason Roszik, Patrick Hwu, Elizabeth A. Grimm, Chantale Bernatchez, Suhendan Ekmekcioglu. CD74 regulated inflammatory pattern is associated with TIL growth and favorable response to adoptive immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR15.