Frontiers in Oncology (Apr 2022)
Intra-Tumoral CD8+ T-Cell Infiltration and PD-L1 Positivity in Homologous Recombination Deficient Pancreatic Ductal Adenocarcinoma
- Bryn Golesworthy,
- Bryn Golesworthy,
- Yifan Wang,
- Yifan Wang,
- Yifan Wang,
- Amanda Tanti,
- Amanda Tanti,
- Alain Pacis,
- Alain Pacis,
- Joan Miguel Romero,
- Joan Miguel Romero,
- Adeline Cuggia,
- Adeline Cuggia,
- Celine Domecq,
- Celine Domecq,
- Guillaume Bourdel,
- Guillaume Bourdel,
- Robert E. Denroche,
- Gun Ho Jang,
- Robert C. Grant,
- Ayelet Borgida,
- Barbara T. Grünwald,
- Anna Dodd,
- Julie M. Wilson,
- Guillaume Bourque,
- Guillaume Bourque,
- Grainne M. O’Kane,
- Grainne M. O’Kane,
- Sandra E. Fischer,
- Sandra E. Fischer,
- Chelsea Maedler Kron,
- Chelsea Maedler Kron,
- Pierre-Olivier Fiset,
- Pierre-Olivier Fiset,
- Atilla Omeroglu,
- Atilla Omeroglu,
- William D. Foulkes,
- William D. Foulkes,
- Steven Gallinger,
- Steven Gallinger,
- Steven Gallinger,
- Marie-Christine Guiot,
- Marie-Christine Guiot,
- Zu-Hua Gao,
- Zu-Hua Gao,
- George Zogopoulos,
- George Zogopoulos,
- George Zogopoulos
Affiliations
- Bryn Golesworthy
- The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Bryn Golesworthy
- The Rosalind and Morris Goodman Cancer Institute of McGill University, Montreal, QC, Canada
- Yifan Wang
- The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Yifan Wang
- The Rosalind and Morris Goodman Cancer Institute of McGill University, Montreal, QC, Canada
- Yifan Wang
- The Department of Surgery, McGill University, Montreal, QC, Canada
- Amanda Tanti
- The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Amanda Tanti
- The Rosalind and Morris Goodman Cancer Institute of McGill University, Montreal, QC, Canada
- Alain Pacis
- The Rosalind and Morris Goodman Cancer Institute of McGill University, Montreal, QC, Canada
- Alain Pacis
- The McGill Genome Center and Canadian Centre for Computational Genomics (C3G), Montreal, QC, Canada
- Joan Miguel Romero
- The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Joan Miguel Romero
- The Rosalind and Morris Goodman Cancer Institute of McGill University, Montreal, QC, Canada
- Adeline Cuggia
- The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Adeline Cuggia
- The Rosalind and Morris Goodman Cancer Institute of McGill University, Montreal, QC, Canada
- Celine Domecq
- The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Celine Domecq
- The Rosalind and Morris Goodman Cancer Institute of McGill University, Montreal, QC, Canada
- Guillaume Bourdel
- The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Guillaume Bourdel
- The Rosalind and Morris Goodman Cancer Institute of McGill University, Montreal, QC, Canada
- Robert E. Denroche
- The Ontario Institute for Cancer Research, Toronto, ON, Canada
- Gun Ho Jang
- The Ontario Institute for Cancer Research, Toronto, ON, Canada
- Robert C. Grant
- The Ontario Institute for Cancer Research, Toronto, ON, Canada
- Ayelet Borgida
- The Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Barbara T. Grünwald
- The Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Anna Dodd
- The Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Julie M. Wilson
- The Ontario Institute for Cancer Research, Toronto, ON, Canada
- Guillaume Bourque
- The McGill Genome Center and Canadian Centre for Computational Genomics (C3G), Montreal, QC, Canada
- Guillaume Bourque
- The Department of Human Genetics, McGill University, Montreal, QC, Canada
- Grainne M. O’Kane
- The Ontario Institute for Cancer Research, Toronto, ON, Canada
- Grainne M. O’Kane
- The Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Sandra E. Fischer
- The Ontario Institute for Cancer Research, Toronto, ON, Canada
- Sandra E. Fischer
- The Division of Pathology, University Health Network, Toronto, ON, Canada
- Chelsea Maedler Kron
- The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Chelsea Maedler Kron
- 0The Department of Pathology, McGill University, Montreal, QC, Canada
- Pierre-Olivier Fiset
- The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Pierre-Olivier Fiset
- 0The Department of Pathology, McGill University, Montreal, QC, Canada
- Atilla Omeroglu
- The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Atilla Omeroglu
- 0The Department of Pathology, McGill University, Montreal, QC, Canada
- William D. Foulkes
- The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- William D. Foulkes
- The Department of Human Genetics, McGill University, Montreal, QC, Canada
- Steven Gallinger
- The Ontario Institute for Cancer Research, Toronto, ON, Canada
- Steven Gallinger
- The Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Steven Gallinger
- The Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Marie-Christine Guiot
- The Rosalind and Morris Goodman Cancer Institute of McGill University, Montreal, QC, Canada
- Marie-Christine Guiot
- 0The Department of Pathology, McGill University, Montreal, QC, Canada
- Zu-Hua Gao
- The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Zu-Hua Gao
- 0The Department of Pathology, McGill University, Montreal, QC, Canada
- George Zogopoulos
- The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- George Zogopoulos
- The Rosalind and Morris Goodman Cancer Institute of McGill University, Montreal, QC, Canada
- George Zogopoulos
- The Department of Surgery, McGill University, Montreal, QC, Canada
- DOI
- https://doi.org/10.3389/fonc.2022.860767
- Journal volume & issue
-
Vol. 12
Abstract
The immune contexture of pancreatic ductal adenocarcinoma (PDAC) is generally immunosuppressive. A role for immune checkpoint inhibitors (ICIs) in PDAC has only been demonstrated for the rare and hypermutated mismatch repair (MMR) deficient (MMR-d) subtype. Homologous recombination repair (HR) deficient (HR-d) PDAC is more prevalent and may encompass up to 20% of PDAC. Its genomic instability may promote a T-cell mediated anti-tumor response with therapeutic sensitivity to ICIs. To investigate the immunogenicity of HR-d PDAC, we used multiplex immunohistochemistry (IHC) to compare the density and spatial distribution of CD8+ cytotoxic T-cells, FOXP3+ regulatory T-cells (Tregs), and CD68+ tumor-associated macrophages (TAMs) in HR-d versus HR/MMR-intact PDAC. We also evaluated the IHC positivity of programmed death-ligand 1 (PD-L1) across the subgroups. 192 tumors were evaluated and classified as HR/MMR-intact (n=166), HR-d (n=25) or MMR-d (n=1) based on germline testing and tumor molecular hallmarks. Intra-tumoral CD8+ T-cell infiltration was higher in HR-d versus HR/MMR-intact PDAC (p<0.0001), while CD8+ T-cell densities in the peri-tumoral and stromal regions were similar in both groups. HR-d PDAC also displayed increased intra-tumoral FOXP3+ Tregs (p=0.049) and had a higher CD8+:FOXP3+ ratio (p=0.023). CD68+ TAM expression was similar in HR-d and HR/MMR-intact PDAC. Finally, 6 of the 25 HR-d cases showed a PD-L1 Combined Positive Score of >=1, whereas none of the HR/MMR-intact cases met this threshold (p<0.00001). These results provide immunohistochemical evidence for intra-tumoral CD8+ T-cell enrichment and PD-L1 positivity in HR-d PDAC, suggesting that HR-d PDAC may be amenable to ICI treatment strategies.
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