Pancreatic Tumor Signal Blocks T-Cell Infiltration, Immunotherapy

Immune T-cell infiltration of pancreatic adenocarcinomas is inhibited in part by tumor production of the chemokine ligand CXCL1, impairing the efficacy of treatment with immune checkpoint inhibitors, according to a preclinical study published in Immunity.

“Tumor cell–intrinsic factors shape the tumor immune microenvironment and influence the outcome of immunotherapy,” concluded senior study author Ben Z. Stanger, MD, PhD, of the Perelman School of Medicine at the University of Pennsylvania, and coauthors. Stanger is director of the Penn Medicine Abramson Cancer Center Pancreatic Cancer Research Center, in Philadelphia.

“Multiple mechanisms contribute to immune heterogeneity,” he and his coauthors cautioned.

Immune checkpoint inhibition has yielded sometimes dramatic tumor responses for patients with solid tumors; however, most patients do not benefit, and tumors evolve resistance to immunotherapy over time. It has been unclear why some tumors respond well to immunotherapy while others do not.

Pancreatic ductal adenocarcinoma (PDA) is expected to become a leading cause of cancer death within a decade, the authors noted. Understanding the molecular factors underlying variation in PDA tumor immunogenicity is a pressing research priority. As with skin cancer responses to immunotherapy, previous studies have also shown that CD8+ T-cell infiltration–rich (“hot”) PDA tumors may be more sensitive to immunotherapy.

The authors engineered a library of congenic tumor cell lines from a mouse model of pancreatic adenocarcinoma. Transplanted into immunocompetent mice, the tumor cell line clones grew into both “hot” or T-cell-inflamed tumor microenvironments, with a high degree of immune T-cell infiltration, and “cold” or non–T-cell-inflamed tumor microenvironments. CD8+ T-cell tumor infiltration predicted response to immunotherapy.

Tumor cell production of the chemokine (C-X-C motif) ligand 1 (CXCL1) recruited myeloid cell infiltration of tumors but inhibited T-cell infiltration, causing resistance to immunotherapy. When CXCL1 genes were knocked out in cold tumor cell lines, CD8+ T-cell infiltration-and sensitivity to immunotherapy-were restored.

“These data suggest that tumor cell–derived CXCL1 is necessary and sufficient to promote the recruitment of suppressive myeloid cells into the PDA, thereby suppressing the infiltration of CD8+ T cells.”

Half of the mice with “hot” tumors (high levels of T-cell infiltration) responded to immune checkpoint inhibition. The addition of chemotherapy, an anti-CD40 agonist, and both chemotherapy and anti-CD40 agonist to checkpoint blockade enhanced that antitumor effect, the authors reported. Twenty of 26 mice with hot tumors treated with chemoimmunotherapy experienced a durable tumor response and survived more than 6 months.

When CXCL1-positive tumors were transplanted to mice that had been cured of primary CXCL1-negative tumors, “most rejected the secondary tumor…[and this was] indicative of a protective [immune] memory response,” they reported.

“Other tumor-cell-intrinsic factors are likely to contribute to the establishment of a T-cell-low tumor microenvironment-each one playing a greater or lesser role in any given tumor,” the authors reported.

The study was funded by the US National Institutes of Health, the Parker Institute for Cancer Immunotherapy, the William C. and Joyce C. O’Neil Charitable Trust, and the Memorial Sloan Kettering Single Cell Sequencing Initiative.