Tumor-intrinsic PIK3CA represses tumor immunogenicity in a model of pancreatic cancer

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Abstract

The presence of tumor-infiltrating T cells is associated with favorable patient outcomes, yet most pancreatic cancers are immunologically silent and resistant to currently available immunotherapies. Here we show using a syngeneic orthotopic implantation model of pancreatic cancer that Pik3ca regulates tumor immunogenicity. Genetic silencing of Pik3ca in Kras ^G12D/Trp53 ^R172H -driven pancreatic tumors resulted in infiltration of T cells, complete tumor regression, and 100% survival of immunocompetent host mice. By contrast, Pik3ca-null tumors implanted in T cell–deficient mice progressed and killed all of the animals. Adoptive transfer of tumor antigen–experienced T cells eliminated Pik3ca-null tumors in immunodeficient mice. Loss of PIK3CA or inhibition of its effector AKT increased the expression of MHC class I and CD80 on tumor cells. These changes contributed to the increased susceptibility of Pik3ca-null tumors to T cell surveillance. Our results indicate that tumor cell PIK3CA-AKT signaling limits T cell recognition and clearance of pancreatic cancer cells. Strategies that target this pathway may yield an effective immunotherapy for this cancer.

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Dynamics of the immune reaction to pancreatic cancer from inception to invasion.

Carolyn Clark, Sunil R Hingorani, Rosemarie Mick … (2007)

The dynamics of cancer immunosurveillance remain incompletely understood, hampering efforts to develop immunotherapy of cancer. We evaluated the evolving in vivo immune response to a spontaneous tumor in a genetically defined mouse model of pancreatic ductal adenocarcinoma from the inception of preinvasive disease to invasive cancer. We observed a prominent leukocytic infiltration even around the lowest grade preinvasive lesions, but immunosuppressive cells, including tumor-associated macrophages, myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg), dominated the early response and persisted through invasive cancer. Effector T cells, however, were scarce in preinvasive lesions, found in only a subset of advanced cancers, and showed no evidence of activation. The lack of tumor-infiltrating effector T cells strongly correlated with the presence of intratumoral MDSC with a near mutual exclusion. In vitro, we found that MDSC suppressed T-cell proliferation. Overall, our results show that suppressive cells of the host immune system appear early during pancreatic tumorigenesis, preceding and outweighing antitumor cellular immunity, and likely contribute to disease progression. Thus, in contrast to the hypothesis that an early "elimination phase" of cancer immunosurveillance is eventually overwhelmed by a growing invasive tumor, our findings suggest that productive tumor immunity may be undermined from the start. Efforts to test potent inhibitors of MDSC, tumor-associated macrophages, and Treg, particularly early in the disease represent important next steps for developing novel immunotherapy of cancer.

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CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes.

Edith Janssen, Edward E. Lemmens, Tom Wolfe … (2003)

A long-standing paradox in cellular immunology concerns the conditional requirement for CD4+ T-helper (T(H)) cells in the priming of cytotoxic CD8+ T lymphocyte (CTL) responses in vivo. Whereas CTL responses against certain viruses can be primed in the absence of CD4+ T cells, others, such as those mediated through 'cross-priming' by host antigen-presenting cells, are dependent on T(H) cells. A clearer understanding of the contribution of T(H) cells to CTL development has been hampered by the fact that most T(H)-independent responses have been demonstrated ex vivo as primary cytotoxic effectors, whereas T(H)-dependent responses generally require secondary in vitro re-stimulation for their detection. Here, we have monitored the primary and secondary responses of T(H)-dependent and T(H)-independent CTLs and find in both cases that CD4+ T cells are dispensable for primary expansion of CD8+ T cells and their differentiation into cytotoxic effectors. However, secondary CTL expansion (that is, a secondary response upon re-encounter with antigen) is wholly dependent on the presence of T(H) cells during, but not after, priming. Our results demonstrate that T-cell help is 'programmed' into CD8+ T cells during priming, conferring on these cells a hallmark of immune response memory: the capacity for functional expansion on re-encounter with antigen.

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Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma.

Abasi Ene-Obong, Andrew Clear, Jennifer Watt … (2013)

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic microenvironment that contains many different immune cells. Activated pancreatic stellate cells (PSCs) contribute to the desmoplasia. We investigated whether distinct stromal compartments are differentially infiltrated by different types of immune cells. We used tissue microarray analysis to compare immune cell infiltration of different pancreaticobiliary diseased tissues (PDAC, ampullary carcinoma, cholangiocarcinoma, mucinous cystic neoplasm, chronic inflammation, and chronic pancreatitis) and juxtatumoral stromal (<100 μm from tumor) and panstromal compartments. We investigated the association between immune infiltrate and patient survival times. We also analyzed T-cell migration and tumor infiltration in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice and the effects of all-trans retinoic acid (ATRA) on these processes. Juxtatumoral compartments in PDAC samples from 2 independent groups of patients contained increased numbers of myeloperoxidase(+) and CD68(+) cells compared with panstromal compartments. However, juxtatumoral compartments of PDACs contained fewer CD8(+), FoxP3(+), CD56(+), or CD20(+) cells than panstromal compartments, a distinction absent in ampullary carcinomas and cholangiocarcinomas. Patients with PDACs that had high densities of CD8(+) T cells in the juxtatumoral compartment had longer survival times than patients with lower densities. In KPC mice, administration of ATRA, which renders PSCs quiescent, increased numbers of CD8(+) T cells in juxtatumoral compartments. We found that activated PSCs express cytokines, chemokines, and adhesion molecules that regulate T-cell migration. In vitro migration assays showed that CD8(+) T cells, from patients with PDAC, had increased chemotaxis toward activated PSCs, which secrete CXCL12, compared with quiescent PSCs or tumor cells. These effects could be reversed by knockdown of CXCL12 or treatment of PSCs with ATRA. Based on studies of human PDAC samples and KPC mice, activated PSCs appear to reduce migration of CD8(+) T cells to juxtatumoral stromal compartments, preventing their access to cancer cells. Deregulated signaling by activated PSCs could prevent an effective antitumor immune response. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Nithya Sivaram

Patrick A. McLaughlin

Han V. Han

Oleksi Petrenko

Ya-Ping Jiang

Lisa M. Ballou:

ORCID: http://orcid.org/0000-0002-5335-6882

Kien Pham

Chen Liu

Adrianus W.M. van der Velden

Richard Z. Lin

Journal

Journal ID (nlm-ta): J Clin Invest

Journal ID (iso-abbrev): J. Clin. Invest

Journal ID (publisher-id): J Clin Invest

Title: The Journal of Clinical Investigation

Publisher: American Society for Clinical Investigation

ISSN (Print): 0021-9738

ISSN (Electronic): 1558-8238

Publication date (Electronic, pub): 15 July 2019

Publication date (Electronic, collection): 15 July 2019

Publication date (Print, pub): 1 August 2019

Publication date PMC-release: 1 August 2019

Volume: 129

Issue: 8

Pages: 3264-3276

Affiliations

[1 ]Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York, USA.

[2 ]Molecular and Cellular Biology Graduate Program, Stony Brook University, Stony Brook, New York, USA.

[3 ]Department of Molecular Genetics and Microbiology and Center for Infectious Diseases, Stony Brook University, Stony Brook, New York, USA.

[4 ]Biomedical Engineering Graduate Program, Stony Brook University, Stony Brook, New York, USA.

[5 ]Department of Pathology and Laboratory Medicine, New Jersey Medical School and Robert Wood Johnson Medical School, Rutgers University School of Medicine, Newark, New Jersey, USA.

[6 ]Medical Service, Northport VA Medical Center, Northport, New York, USA.

Author notes

Address correspondence to: Richard Z. Lin, Department of Physiology & Biophysics, BST 6-183, Stony Brook University, Stony Brook, New York 11794-8661. Phone: 631.444.1638; Email: richard.lin@ 123456stonybrook.edu .

Author information

Lisa M. Ballou http://orcid.org/0000-0002-5335-6882

Article

Publisher ID: 123540

DOI: 10.1172/JCI123540

PMC ID: 6668699

PubMed ID: 31112530

SO-VID: f6a9922d-8150-4008-a572-24a465666707

License:

This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 12 July 2018

Date accepted : 16 May 2019

Funding

Funded by: U.S. Department of Veterans Affairs, https://doi.org/10.13039/100000738;

Award ID: BX004083

Funded by: National Cancer Institute, https://doi.org/10.13039/100000054;

Award ID: CA194836

Funded by: National Institute of Diabetes and Digestive and Kidney Diseases, https://doi.org/10.13039/100000062;

Tumor-intrinsic PIK3CA represses tumor immunogenicity in a model of pancreatic cancer

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Cancer Immunotherapy

Most cited references 49

Dynamics of the immune reaction to pancreatic cancer from inception to invasion.

CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes.

Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma.

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