Advertisement

Cancer Immunology, Immunotherapy

, Volume 66, Issue 12, pp 1609–1617 | Cite as

CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer

  • Fee Bengsch
  • Dawson M. Knoblock
  • Anni Liu
  • Florencia McAllister
  • Gregory L. BeattyEmail author
Original Article

Abstract

The ability of some tumors to exclude effector T cells represents a major challenge to immunotherapy. T cell exclusion is particularly evident in pancreatic ductal adenocarcinoma (PDAC), a disease where blockade of the immune checkpoint molecule CTLA-4 has not produced significant clinical activity. In PDAC, effector T cells are often scarce within tumor tissue and confined to peritumoral lymph nodes and lymphoid aggregates. We hypothesized that CTLA-4 blockade, despite a lack of clinical efficacy seen thus far in PDAC, might still alter T cell immunobiology, which would have therapeutic implications. Using clinically relevant genetic models of PDAC, we found that regulatory T cells (Tregs), which constitutively express CTLA-4, accumulate early during tumor development but are largely confined to peritumoral lymph nodes during disease progression. Tregs were observed to regulate CD4+, but not CD8+, T cell infiltration into tumors through a CTLA-4/CD80 dependent mechanism. Disrupting CTLA-4 interaction with CD80 was sufficient to induce CD4 T cell infiltration into tumors. These data have important implications for T cell immunotherapy in PDAC and demonstrate a novel role for CTLA-4/CD80 interactions in regulating T cell exclusion. In addition, our findings suggest distinct mechanisms govern CD4+ and CD8+ T cell infiltration in PDAC.

Keywords

Pancreas cancer T cell exclusion Treg CTLA-4 CD80 Immunotherapy 

Abbreviations

CiMist1

Mist1CreERT2

CTLA-4

Cytotoxic lymphocyte-associated antigen-4

DAB

3,3′-Diaminobenzidine

DC

Dendritic cell

KCiMist1

Mist1CreERT2;LSL-Kras G12D/+

KPC

LSL-Kras G12D/+;LSL-Trp53 R172H/+; Pdx-1Cre

PanIN

Pancreatic intraepithelial neoplasia

PC

LSL-Trp53 R172H/+;Pdx-1Cre

PDAC

Pancreatic ductal adenocarcinoma

Treg

Regulatory T cell

Notes

Acknowledgements

The authors thank Patrick Guirnalda for helpful discussion and Adam Bedenbaugh for advice and technical assistance with immunohistochemistry assays.

Compliance with ethical standards

Financial support

Support for this project was provided by the following grants from the National Institutes of Health and National Cancer Institute: K08 CA138907 (Gregory L. Beatty) and R01 CA197916 (Gregory L. Beatty). We are grateful to the Molecular Biology and Molecular Pathology and Imaging Cores of the Penn Center supported by a Molecular Studies in Digestive and Liver Diseases grant from the National Institutes of Health. This work was also supported by the following foundations and agencies: AACR-PanCAN Career Development Award (Florencia McAllister), National Pancreas Foundation (Florencia McAllister), Department of Defense Discovery Award (Gregory Beatty), and the Damon Runyon Cancer Research Foundation Innovation Award supported by the Nadia’s Gift Foundation (Gregory Beatty).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

262_2017_2053_MOESM1_ESM.pdf (1.1 mb)
Supplementary material 1 (PDF 1089 kb)

References

  1. 1.
    Beatty GL, O’Hara MH, Nelson AM et al (2015) Safety and antitumor activity of chimeric antigen receptor modified T cells in patients with chemotherapy refractory metastatic pancreatic cancer. J Clin Oncol 33:3007Google Scholar
  2. 2.
    Beatty GL, Haas AR, Maus MV et al (2014) Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce antitumor activity in solid malignancies. Cancer Immunol Res 2:112–120CrossRefPubMedGoogle Scholar
  3. 3.
    Le DT, Lutz E, Uram JN et al (2013) Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother 36:382–389CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Le DT, Wang-Gillam A, Picozzi V et al (2015) Safety and survival with GVAX pancreas prime and listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol 33:1325–1333CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Royal RE, Levy C, Turner K et al (2010) Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 33:828–833CrossRefPubMedGoogle Scholar
  6. 6.
    Brahmer JR, Tykodi SS, Chow LQ et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Beatty GL, Gladney WL (2015) Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res 21:687–692CrossRefPubMedGoogle Scholar
  8. 8.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    McCoy KD, Le Gros G (1999) The role of CTLA-4 in the regulation of T cell immune responses. Immunol Cell Biol 77:1–10CrossRefPubMedGoogle Scholar
  10. 10.
    Schadendorf D, Hodi FS, Robert C et al (2015) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 33:1889–1894CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Aglietta M, Barone C, Sawyer MB et al (2014) A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. Ann Oncol 25:1750–1755CrossRefPubMedGoogle Scholar
  12. 12.
    Habbe N, Shi G, Meguid RA et al (2008) Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proc Natl Acad Sci USA 105:18913–18918CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, Rustgi AK, Chang S, Tuveson DA (2005) Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7:469–483CrossRefPubMedGoogle Scholar
  14. 14.
    Beatty GL, Chiorean EG, Fishman MP et al (2011) CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331:1612–1616CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Uhlen M, Fagerberg L, Hallstrom BM et al (2015) Proteomics. Tissue-based map of the human proteome. Science 347:1260419CrossRefPubMedGoogle Scholar
  16. 16.
    Uhlen M, Bjorling E, Agaton C et al (2005) A human protein atlas for normal and cancer tissues based on antibody proteomics. Mol Cell Proteom 4:1920–1932CrossRefGoogle Scholar
  17. 17.
    Long KB, Gladney WL, Tooker GM, Graham K, Fraietta JA, Beatty GL (2016) IFNgamma and CCL2 cooperate to redirect tumor-infiltrating monocytes to degrade fibrosis and enhance chemotherapy efficacy in pancreatic carcinoma. Cancer Discov 6:400–413CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Allan SE, Crome SQ, Crellin NK, Passerini L, Steiner TS, Bacchetta R, Roncarolo MG, Levings MK (2007) Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol 19:345–354CrossRefPubMedGoogle Scholar
  19. 19.
    Devaud C, Darcy PK, Kershaw MH (2014) Foxp3 expression in T regulatory cells and other cell lineages. Cancer Immunol Immunother 63:869–876CrossRefPubMedGoogle Scholar
  20. 20.
    McAllister F, Bailey JM, Alsina J et al (2014) Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. Cancer Cell 25:621–637CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Rech AJ, Mick R, Martin S et al (2012) CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci Transl Med. 4:134CrossRefGoogle Scholar
  22. 22.
    Schmidt EM, Wang CJ, Ryan GA et al (2009) Ctla-4 controls regulatory T cell peripheral homeostasis and is required for suppression of pancreatic islet autoimmunity. J Immunol 182:274–282CrossRefPubMedGoogle Scholar
  23. 23.
    Grohmann U, Orabona C, Fallarino F et al (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 3:1097–1101CrossRefPubMedGoogle Scholar
  24. 24.
    Teft WA, Kirchhof MG, Madrenas J (2006) A molecular perspective of CTLA-4 function. Annu Rev Immunol 24:65–97CrossRefPubMedGoogle Scholar
  25. 25.
    Huang RR, Jalil J, Economou JS et al (2011) CTLA4 blockade induces frequent tumor infiltration by activated lymphocytes regardless of clinical responses in humans. Clin Cancer Res 17:4101–4109CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E (1999) Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 59:3128–3133PubMedGoogle Scholar
  27. 27.
    Stromnes IM, Schmitt TM, Hulbert A et al (2015) T cells engineered against a native antigen can surmount immunologic and physical barriers to treat pancreatic ductal adenocarcinoma. Cancer Cell 28:638–652CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Feig C, Jones JO, Kraman M et al (2013) Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci USA 110:20212–20217CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Onishi Y, Fehervari Z, Yamaguchi T, Sakaguchi S (2008) Foxp3 + natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc Natl Acad Sci USA 105:10113–10118CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Qureshi OS, Zheng Y, Nakamura K et al (2011) Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332:600–603CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Zheng Y, Manzotti CN, Liu M, Burke F, Mead KI, Sansom DM (2004) CD86 and CD80 differentially modulate the suppressive function of human regulatory T cells. J Immunol 172:2778–2784CrossRefPubMedGoogle Scholar
  32. 32.
    Matheu MP, Othy S, Greenberg ML et al (2015) Imaging regulatory T cell dynamics and CTLA4-mediated suppression of T cell priming. Nat Commun 6:6219CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Bauer CA, Kim EY, Marangoni F, Carrizosa E, Claudio NM, Mempel TR (2014) Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction. J Clin Invest 124:2425–2440CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Beatty GL, Winograd R, Evans RA et al (2015) Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6C (low) F4/80(+) extratumoral macrophages. Gastroenterology 149:201–210CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Alexandrov LB, Nik-Zainal S, Wedge DC et al (2013) Signatures of mutational processes in human cancer. Nature 500:415–421CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39:1–10CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Fee Bengsch
    • 1
    • 2
  • Dawson M. Knoblock
    • 1
    • 2
  • Anni Liu
    • 1
    • 2
  • Florencia McAllister
    • 3
  • Gregory L. Beatty
    • 1
    • 2
    • 4
    Email author
  1. 1.Abramson Cancer CenterUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Division of Hematology-Oncology, Department of Medicine, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Department of Clinical Cancer PreventionUniversity of Texas MD Anderson Cancer CenterHoustonUSA
  4. 4.Perelman Center for Advanced MedicinePhiladelphiaUSA

Personalised recommendations