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Immunotherapy Response Features Identified in Pancreatic Cancer Microenvironment

NEW YORK – Treatment with the immune checkpoint inhibitor (ICI) immunotherapies targeting the PD-1 protein can significantly alter the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) cases, according to new research by a Johns Hopkins University School of Medicine-led team.

"These findings provide insights into PD-1-regulated immune pathways in PDAC that should inform more effective therapeutic combinations that include [tumor-associated neutrophil] regulators and T cell activators," the investigators wrote in Cancer Cell on Thursday.

The study was led by Lei Zheng, Elizabeth Jaffee, and Elana Fertig, researchers affiliated with the Johns Hopkins University School of Medicine's oncology department, the Sidney Kimmel Comprehensive Cancer Center, and other Johns Hopkins departments.

Using samples collected as part of a clinical trial evaluating a "granulocyte-macrophage colony-stimulating factor-secreting allogeneic PDAC vaccine" (GVAX), the researchers turned to multiplex or singleplex immunohistochemistry, exome sequencing, RNA sequencing, and other approaches to characterize tumor microenvironment features in samples taken from 17 PDAC patients before and after treatment with GVAX, alone, or in combination with the anti-PD-1 drug nivolumab (Bristol Myers Squibb's Opdivo).

The authors explained that they have been testing the hypothesis that cancer vaccines are effective in inducing ICI-responsive effector T cells (Teffs) that can infiltrate PDACs, further noting that it is currently challenging to identify additional immune-regulatory signals within the complex PDAC tumor microenvironment that require further modification to enhance Teff function and to optimize and maintain activation of the most potent Teffs.

Participants considered in the trial were randomized to receive neoadjuvant treatment with GVAX alone or GVAX in combination with nivolumab, followed by surgical tumor resection. The immunotherapy treatment and standard of care adjuvant chemotherapy continued after successful surgery for the nine GVAX-treated patients and eight GVAX- and nivolumab-treated patients.

"This prospectively collected cohort of PDAC paired pre- and post-treatment tumor biospecimens was analyzed to elucidate the mechanisms of anti-PD-1 treatment sensitivity and resistance in the neoadjuvant setting," the authors explained, noting that the work integrates multiomic analyses to comprehensively define changes in immune subsets with PDAC tumor microenvironments following anti-PD-1 ICI therapy.

Along with increased Teff infiltration after combined GVAX and ICIC treatment, the team's findings highlighted tumor microenvironment features that seemed to correspond to enhanced or diminished responses to anti-PD-1 checkpoint immunotherapy, while highlighting microenvironment changes that arise in response to the immunotherapy.

Among other features, the researchers found that higher-than-usual tumor-associated neutrophil densities appeared to coincide with poorer treatment response and overall survival patterns, for example. On the other hand, they saw an apparent overall survival advantage for PDAC cases marked by reduced CD4+PD-1+ and CD8+ PD-1+ T cell representation in lymphoid aggregates and/or increased levels of CD37-expressing T cells and related cytotoxic activated Teff signatures after GVAX-ICI treatment.

The team further teased out post-treatment immune shifts in the tumor microenvironment — from shifts in T-cell signaling to cell type proportions — with the help of available RNA-seq and single-cell RNA-seq data.

"Our integrated analysis approach suggested previously unrealized mechanisms promoting T cell exhaustion following PD-1 antibody therapy," the authors reported, adding that results so far suggest that "multiomic analyses in small cohorts of surgically resectable PDAC patients comparing different immune modulatory agents may be a rapid and efficient way to identify the immunomodulatory effects that can inform combinations for testing in larger studies with primary clinical endpoints."