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. 2019 Jan 29;116(5):1692-1697.
doi: 10.1073/pnas.1811067116. Epub 2019 Jan 11.

Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer

Jorge Blando  1 , Anu Sharma  2 , Maria Gisela Higa  1 , Hao Zhao  1 , Luis Vence  1 , Shalini S Yadav  1 , Jiseong Kim  1 , Alejandro M Sepulveda  3 , Michael Sharp  3 , Anirban Maitra  4   5 , Jennifer Wargo  6 , Michael Tetzlaff  4 , Russell Broaddus  4 , Matthew H G Katz  6 , Gauri R Varadhachary  7 , Michael Overman  7 , Huamin Wang  4 , Cassian Yee  8 , Chantale Bernatchez  8 , Christine Iacobuzio-Donahue  9 , Sreyashi Basu  1 , James P Allison  10   11 , Padmanee Sharma  10   2   11
Affiliations

V体育安卓版 - Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer

VSports app下载 - Jorge Blando et al. Proc Natl Acad Sci U S A. .

Abstract

Immune checkpoint therapy (ICT) has transformed cancer treatment in recent years; however, treatment response is not uniform across tumor types. The tumor immune microenvironment plays a critical role in determining response to ICT; therefore, understanding the differential immune infiltration between ICT-sensitive and ICT-resistant tumor types will help to develop effective treatment strategies. We performed a comprehensive analysis of the immune tumor microenvironment of an ICT-sensitive tumor (melanoma, n = 44) and an ICT-resistant tumor (pancreatic cancer, n = 67). We found that a pancreatic tumor has minimal to moderate infiltration of CD3, CD4, and CD8 T cells; however, the immune infiltrates are predominantly present in the stromal area of the tumor and are excluded from tumoral area compared with melanoma, where the immune infiltrates are primarily present in the tumoral area. Metastatic pancreatic ductal adenocarcinomas (PDACs) had a lower infiltration of total T cells compared with resectable primary PDACs, suggesting that metastatic PDACs have poor immunogenicity. Further, a significantly higher number of CD68+ macrophages and VISTA+ cells (also known as V-domain immunoglobulin suppressor of T cell activation) were found in the pancreatic stromal area compared with melanoma. We identified VISTA as a potent inhibitory checkpoint that is predominantly expressed on CD68+ macrophages on PDACs. These data suggest that VISTA may be a relevant immunotherapy target for effective treatment of patients with pancreatic cancer VSports手机版. .

Keywords: immune checkpoints; immune infiltrate; immune monitoring; immunopathology; pancreatic cancer V体育安卓版. .

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Conflict of interest statement

Conflict of interest statement: J. P. A. is an inventor and recipient of royalties from intellectual property licensed to Bristol-Meyer Squibb, Merck, and Jounce. He is a member of the scientific advisory board for Jounce Therapeutics, Neon Therapeutics, Amgen, Apricity, BioAlta, Forty-Seven, Tvardi Therapeutics, TapImmune, ImaginAB, Codiak Biosciences, and Marker Therapeutics. J. P. A. and P. S. own a patent licensed to Jounce Therapeutics. P V体育ios版. S. serves as a consultant for Constellation, Jounce Therapuetics, Kite Pharma, Neon Therapeutics, BioAtla, Pieris Pharmaceuticals, Oncolytics Biotech, Merck, BioMx, Forty-Seven, Polaris, Apricity, Marker Therapeutics, Codiak, ImaginAB, and TapImmune. She also has stock ownership in Jounce, Neon Therapeutics, Constellation, Oncolytics, BioAtlanta, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, ImaginAB, and TapImmune. A. S. is an employee of Janssen.

Figures

Fig. 1.
Fig. 1.
Expression of T-cell coinhibitory genes correlates with overall survival in pancreatic cancer. (A) PCA showing coinhibitory genes that are associated with the immunogenic subtype of pancreatic cancer (LAG-3, PD-L1, VISTA, BTLA, CTLA-4, TIGIT, TIM-3, CD244, and CD160). Gene expression data from a cohort of 23 untreated pancreatic tumors were analyzed. PCA separated patients into two cohorts: those with high T-cell coinhibitory gene expression (n = 11) and those with low T-cell coinhibitory gene expression (n = 12). (B) Kaplan−Meier survival curves for patients with high (red) or low (blue) T-cell coinhibitory gene expression.
Fig. 2.
Fig. 2.
Comparison of immune infiltrates in the total TME in pancreatic cancer and melanoma. Bar and dot plots comparing immune subsets (CD3, CD4, CD8, and CD68) and immune cells expressing VISTA, PD-1, and PD-L1 evaluated by IHC at 10× (large square) and 20× (small square) magnification. Each dot represents a patient, and bars with lines indicate median with confidence interval (CI). Only significant P values between groups are indicated. Statistical significance is defined as P < 0.05. **P ≤ 0.01; ***P ≤ 0.001.
Fig. 3.
Fig. 3.
Distribution of immune infiltrates in the tumor and stromal compartments in pancreatic cancer compared with melanoma. (A) Tumor/stroma ratio for each tumor type. (B) Bar plots comparing the median expression of the selected immune subsets (CD3, CD4, CD8, CD68, and VISTA) in each compartment of the total TME. Statistical significance is defined as P < 0.05. *P ≤ 0.05; **P ≤ 0.01; ****P ≤ 0.0001; ns, nonsignificant.
Fig. 4.
Fig. 4.
Immune infiltrates in the total TME in primary untreated, neoadjuvant-treated, and metastatic pancreatic tumors. Bar and dot plots compare immune subsets (CD3, CD4, CD8, CD68, and VISTA) evaluated by IHC. Each dot represents one patient; bars with lines indicate medians with confidence intervals. Only significant P values between groups are indicated. Statistical significance is defined as P < 0.05. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001. ca, cancer.
Fig. 5.
Fig. 5.
CyTOF analysis of CD68, PD-L1, and VISTA expression in human pancreatic tumors. CyTOF data are from a representative primary pancreatic, showing CD68+ macrophages and the inhibitory immune checkpoints PD-L1 and VISTA. Each point on the viSNE maps represents a single cell. Red indicates a high level of marker expression; blue indicates no marker expression.
Fig. 6.
Fig. 6.
Engagement of VISTA inhibits cytokine production by TILs. TILs from metastatic pancreatic tumors (n = 3) were cultured independently in different experiments with plate-bound VISTA−Ig and/or PD-L1−Ig to evaluate the function by CD107a degranulation assay and intracellular cytokine staining for IFN-γ and TNF-α. Data are expressed as mean with SD for the three independent experiments and represent percentage changes after normalization to control Ig. The differences in degranulation and cytokine release are compared with the control Ig group. Only significant P values between groups are indicated. Statistical significance is defined as P < 0.05. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.
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