Neoadjuvant chemoradiation alters the immune microenvironment in pancreatic ductal adenocarcinoma

Robyn D Gartrell; Thomas Enzler; Pan S Kim; Benjamin T Fullerton; Ladan Fazlollahi; Andrew X Chen; Hanna E Minns; Subha Perni; Stuart P Weisberg; Emanuelle M Rizk; Samuel Wang; Eun Jeong Oh; Xinzheng V Guo; Codruta Chiuzan; Gulam A Manji; Susan E Bates; John Chabot; Beth Schrope; Michael Kluger; Jean Emond; Raul Rabadán; Donna Farber; Helen E Remotti; David P Horowitz; Yvonne M Saenger

doi:10.1080/2162402X.2022.2066767

Neoadjuvant chemoradiation alters the immune microenvironment in pancreatic ductal adenocarcinoma

Oncoimmunology. 2022 May 5;11(1):2066767. doi: 10.1080/2162402X.2022.2066767. eCollection 2022.

Authors

Robyn D Gartrell¹, Thomas Enzler², Pan S Kim³, Benjamin T Fullerton⁴, Ladan Fazlollahi⁵, Andrew X Chen⁶, Hanna E Minns¹, Subha Perni⁷, Stuart P Weisberg⁵, Emanuelle M Rizk⁴, Samuel Wang⁴, Eun Jeong Oh⁸, Xinzheng V Guo⁴, Codruta Chiuzan⁹, Gulam A Manji⁴, Susan E Bates⁴, John Chabot¹⁰, Beth Schrope¹⁰, Michael Kluger¹⁰, Jean Emond¹⁰, Raul Rabadán¹¹, Donna Farber¹², Helen E Remotti⁵, David P Horowitz¹³, Yvonne M Saenger¹⁴

Affiliations

¹ Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.
² Rogel Cancer Center, University of Michigan Medicine, Ann Arbor, MI, USA.
³ Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁴ Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
⁵ Department of Pathology, Columbia University Irving Medical Center, New York, NY, USA.
⁶ Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
⁷ Harvard Radiation Oncology Program, Massachusetts General Hospital and Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ Mailman School of Public Health, Columbia University, New York, NY, USA.
⁹ Department of Biostatistics, Columbia University Irving Medical Center, New York, NY, USA.
¹⁰ Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA.
¹¹ Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA.
¹² Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA.
¹³ Department of Radiation Oncology, Columbia University Irving Medical Center, New York, NY, USA.
¹⁴ Albert Einstein College of Medicine, Columbia University.

Abstract

Patients with pancreatic ductal adenocarcinoma (PDAC) have a grim prognosis despite complete surgical resection and intense systemic therapies. While immunotherapies have been beneficial with many different types of solid tumors, they have almost uniformly failed in the treatment of PDAC. Understanding how therapies affect the tumor immune microenvironment (TIME) can provide insights for the development of strategies to treat PDAC. We used quantitative multiplexed immunofluorescence (qmIF) quantitative spatial analysis (qSA), and immunogenomic (IG) analysis to analyze formalin-fixed paraffin embedded (FFPE) primary tumor specimens from 44 patients with PDAC including 18 treated with neoadjuvant chemoradiation (CRT) and 26 patients receiving no treatment (NT) and compared them with tissues from 40 treatment-naïve melanoma patients. We find that relative to NT tumors, CD3⁺ T cell infiltration was increased in CRT treated tumors (p = .0006), including increases in CD3⁺CD8⁺ cytotoxic T cells (CTLs, p = .0079), CD3⁺CD4⁺FOXP3^- T helper cells (T_h, p = .0010), and CD3⁺CD4⁺FOXP3⁺ regulatory T cells (Tregs, p = .0089) with no difference in CD68⁺ macrophages. IG analysis from micro-dissected tissues indicated overexpression of genes involved in antigen presentation, T cell activation, and inflammation in CRT treated tumors. Among treated patients, a higher ratio of Tregs to total T cells was associated with shorter survival time (p = .0121). Despite comparable levels of infiltrating T cells in CRT PDACs to melanoma, PDACs displayed distinct spatial profiles with less T cell clustering as defined by nearest neighbor analysis (p < .001). These findings demonstrate that, while CRT can achieve high T cell densities in PDAC compared to melanoma, phenotype and spatial organization of T cells may limit benefit of T cell infiltration in this immunotherapy-resistant tumor.

Keywords: T regulatory cells; Tumor microenvironment; biomarkers; tumor-infiltrating lymphocytes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Pancreatic Ductal* / genetics
Carcinoma, Pancreatic Ductal* / pathology
Carcinoma, Pancreatic Ductal* / therapy
Forkhead Transcription Factors
Humans
Melanoma* / therapy
Neoadjuvant Therapy
Pancreatic Neoplasms* / therapy
Tumor Microenvironment

Substances

Forkhead Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding