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Combined sublethal irradiation and agonist anti-CD40 enhance donor T cell accumulation and control of autochthonous murine pancreatic tumors

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Abstract

Tumor-reactive T lymphocytes can promote the regression of established tumors. However, their efficacy is often limited by immunosuppressive mechanisms that block T cell accumulation or function. ACT provides the opportunity to ameliorate immune suppression prior to transfer of tumor-reactive T cells to improve the therapeutic benefit. We evaluated the combination of lymphodepleting whole body irradiation (WBI) and agonist anti-CD40 (αCD40) antibody on control of established autochthonous murine neuroendocrine pancreatic tumors following the transfer of naïve tumor-specific CD8 T cells. Sublethal WBI had little impact on disease outcome but did promote T cell persistence in the lymphoid organs. Host conditioning with αCD40, an approach known to enhance APC function and T cell expansion, transiently increased donor T cell accumulation in the lymphoid organs and pancreas, but failed to control tumor progression. In contrast, combined WBI and αCD40 prolonged T cell proliferation and dramatically enhanced accumulation of donor T cells in both the lymphoid organs and pancreas. This dual conditioning approach also promoted high levels of inflammation in the pancreas and tumor, induced histological regression of established tumors, and extended the lifespan of treated mice. Prolonged survival was entirely dependent upon adoptive transfer, but only partially dependent upon IFNγ production by donor T cells. Our results identify the novel combination of two clinically relevant host conditioning approaches that synergize to overcome immune suppression and drive strong tumor-specific T cell accumulation within well-established tumors.

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Abbreviations

αCD40:

Anti-CD40

gB:

Glycoprotein B

GKO:

Interferon gamma knockout

Gy:

Gray

PLN:

Pancreaticoduodenal lymph node

RT4:

Rip1-Tag4

T Ag:

T antigen

TetI:

H-2Db/I tetramer

TRAMP:

Transgenic adenocarcinoma of the mouse prostate

WBI:

Whole body irradiation

References

  1. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964. https://doi.org/10.1126/science.1129139

    Article  CAS  PubMed  Google Scholar 

  2. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568–571. https://doi.org/10.1038/nature13954

    Article  Google Scholar 

  3. Gajewski TF, Woo SR, Zha Y, Spaapen R, Zheng Y, Corrales L, Spranger S (2013) Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr Opin Immunol 25:268–276. https://doi.org/10.1016/j.coi.2013.02.009

    Google Scholar 

  4. Hinrichs CS, Rosenberg SA (2014) Exploiting the curative potential of adoptive T-cell therapy for cancer. Immunol Rev 257:56–71. https://doi.org/10.1111/imr.12132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Klebanoff CA, Khong HT, Antony PA, Palmer DC, Restifo NP (2005) Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol 26:111–117. https://doi.org/10.1016/j.it.2004.12.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Goff SL, Dudley ME, Citrin DE, Somerville RP, Wunderlich JR, Danforth DN, Zlott DA, Yang JC, Sherry RM, Kammula US, Klebanoff CA, Hughes MS, Restifo NP, Langhan MM, Shelton TE, Lu L, Kwong ML, Ilyas S, Klemen ND, Payabyab EC, Morton KE, Toomey MA, Steinberg SM, White DE, Rosenberg SA (2016) Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma. J Clin Oncol 34:2389–2397. https://doi.org/10.1200/JCO.2016.66.7220

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cozza EM, Cooper TK, Budgeon LR, Christensen ND, Schell TD (2015) Protection from tumor recurrence following adoptive immunotherapy varies with host conditioning regimen despite initial regression of autochthonous murine brain tumors. Cancer Immunol Immunother 64:325–336. https://doi.org/10.1007/s00262-014-1635-7

    Article  Google Scholar 

  8. Staveley-O’Carroll K, Schell TD, Jimenez M, Mylin LM, Tevethia MJ, Schoenberger SP, Tevethia SS (2003) In vivo ligation of CD40 enhances priming against the endogenous tumor antigen and promotes CD8 + T cell effector function in SV40 T antigen transgenic mice. J Immunol 171:697–707

    Article  PubMed  Google Scholar 

  9. Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y, Yagita H, Overwijk WW, Lizee G, Radvanyi L, Hwu P (2012) PD-1 blockade enhances T-cell migration to tumors by elevating IFN-gamma inducible chemokines. Cancer Res 72:5209–5218. https://doi.org/10.1158/0008-5472.CAN-12-1187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Shrikant P, Khoruts A, Mescher MF (1999) CTLA-4 blockade reverses CD8 + T cell tolerance to tumor by a CD4 + T cell- and IL-2-dependent mechanism. Immunity 11:483–493

    Article  Google Scholar 

  11. John LB, Devaud C, Duong CP, Yong CS, Beavis PA, Haynes NM, Chow MT, Smyth MJ, Kershaw MH, Darcy PK (2013) Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res 19:5636–5646. https://doi.org/10.1158/1078-0432.CCR-13-0458

    Article  CAS  PubMed  Google Scholar 

  12. Nobuoka D, Yoshikawa T, Takahashi M, Iwama T, Horie K, Shimomura M, Suzuki S, Sakemura N, Nakatsugawa M, Sadamori H, Yagi T, Fujiwara T, Nakatsura T (2013) Intratumoral peptide injection enhances tumor cell antigenicity recognized by cytotoxic T lymphocytes: a potential option for improvement in antigen-specific cancer immunotherapy. Cancer Immunol Immunother 62:639–652. https://doi.org/10.1007/s00262-012-1366-6

    Article  Google Scholar 

  13. Klebanoff CA, Gattinoni L, Palmer DC, Muranski P, Ji Y, Hinrichs CS, Borman ZA, Kerkar SP, Scott CD, Finkelstein SE, Rosenberg SA, Restifo NP (2011) Determinants of successful CD8 + T-cell adoptive immunotherapy for large established tumors in mice. Clin Cancer Res 17:5343–5352. https://doi.org/10.1158/1078-0432.CCR-11-0503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Duong CP, Yong CS, Kershaw MH, Slaney CY, Darcy PK (2015) Cancer immunotherapy utilizing gene-modified T cells: from the bench to the clinic. Mol Immunol 67:46–57. https://doi.org/10.1016/j.molimm.2014.12.009

    Article  CAS  PubMed  Google Scholar 

  15. Ganss R, Ryschich E, Klar E, Arnold B, Hammerling GJ (2002) Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication. Cancer Res 62:1462–1470

    CAS  PubMed  Google Scholar 

  16. Klug F, Prakash H, Huber PE, Seibel T, Bender N, Halama N, Pfirschke C, Voss RH, Timke C, Umansky L, Klapproth K, Schakel K, Garbi N, Jager D, Weitz J, Schmitz-Winnenthal H, Hammerling GJ, Beckhove P (2013) Low-dose irradiation programs macrophage differentiation to an iNOS(+)/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 24:589–602. https://doi.org/10.1016/j.ccr.2013.09.014

    Article  CAS  PubMed  Google Scholar 

  17. Gupta A, Probst HC, Vuong V, Landshammer A, Muth S, Yagita H, Schwendener R, Pruschy M, Knuth A, van den Broek M (2012) Radiotherapy promotes tumor-specific effector CD8 + T cells via dendritic cell activation. J Immunol 189:558–566. https://doi.org/10.4049/jimmunol.1200563

    Article  Google Scholar 

  18. Paulos CM, Wrzesinski C, Kaiser A, Hinrichs CS, Chieppa M, Cassard L, Palmer DC, Boni A, Muranski P, Yu Z, Gattinoni L, Antony PA, Rosenberg SA, Restifo NP (2007) Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8 + T cells via TLR4 signaling. J Clin Invest 117:2197–2204. https://doi.org/10.1172/JCI32205

    Article  Google Scholar 

  19. Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A, Li XD, Mauceri H, Beckett M, Darga T, Huang X, Gajewski TF, Chen ZJ, Fu YX, Weichselbaum RR (2014) STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41:843–852. https://doi.org/10.1016/j.immuni.2014.10.019

    Article  Google Scholar 

  20. Lim JY, Gerber SA, Murphy SP, Lord EM (2014) Type I interferons induced by radiation therapy mediate recruitment and effector function of CD8(+) T cells. Cancer Immunol Immunother 63:259–271. https://doi.org/10.1007/s00262-013-1506-7

    Article  Google Scholar 

  21. Tatum AM, Mylin LM, Bender SJ, Fischer MA, Vigliotti BA, Tevethia MJ, Tevethia SS, Schell TD (2008) CD8 + T cells targeting a single immunodominant epitope are sufficient for elimination of established SV40 T antigen-induced brain tumors. J Immunol 181:4406–4417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ward-Kavanagh LK, Zhu J, Cooper TK, Schell TD (2014) Whole-body irradiation increases the magnitude and persistence of adoptively transferred T cells associated with tumor regression in a mouse model of prostate cancer. Cancer Immunol Res 2:777–788. https://doi.org/10.1158/2326-6066.CIR-13-0164

    Article  Google Scholar 

  23. Ryan CM, Staveley-O’Carroll K, Schell TD (2008) Combined anti-CD40 conditioning and well-timed immunization prolongs CD8 + T cell accumulation and control of established brain tumors. J Immunother 31:906–920. https://doi.org/10.1097/CJI.0b013e318189f155

    Article  Google Scholar 

  24. Bennett SR, Carbone FR, Karamalis F, Flavell RA, Miller JF, Heath WR (1998) Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393:478–480. https://doi.org/10.1038/30996

    Article  Google Scholar 

  25. Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G (1996) Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med 184:747–752

    Article  Google Scholar 

  26. Vonderheide RH, Glennie MJ (2013) Agonistic CD40 antibodies and cancer therapy. Clin Cancer Res 19:1035–1043. https://doi.org/10.1158/1078-0432.CCR-12-2064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, Huhn RD, Song W, Li D, Sharp LL, Torigian DA, O’Dwyer PJ, Vonderheide RH (2011) CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331:1612–1616. https://doi.org/10.1126/science.1198443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Beatty GL, Winograd R, Evans RA, Long KB, Luque SL, Lee JW, Clendenin C, Gladney WL, Knoblock DM, Guirnalda PD, Vonderheide RH (2015) Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6C(low) F4/80(+) extratumoral macrophages. Gastroenterology 149:201–210. https://doi.org/10.1053/j.gastro.2015.04.010

    Article  Google Scholar 

  29. Hanahan D (1985) Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315:115–122

    Article  Google Scholar 

  30. Ye X, McCarrick J, Jewett L, Knowles BB (1994) Timely immunization subverts the development of peripheral nonresponsiveness and suppresses tumor development in simian virus 40 tumor antigen-transgenic mice. Proc Natl Acad Sci USA 91:3916–3920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Otahal P, Schell TD, Hutchinson SC, Knowles BB, Tevethia SS (2006) Early immunization induces persistent tumor-infiltrating CD8 + T cells against an immunodominant epitope and promotes lifelong control of pancreatic tumor progression in SV40 tumor antigen transgenic mice. J Immunol 177:3089–3099

    Article  CAS  PubMed  Google Scholar 

  32. Otahal P, Knowles BB, Tevethia SS, Schell TD (2007) Anti-CD40 conditioning enhances the T(CD8) response to a highly tolerogenic epitope and subsequent immunotherapy of simian virus 40 T antigen-induced pancreatic tumors. J Immunol 179:6686–6695

    Article  CAS  PubMed  Google Scholar 

  33. Tevethia SS, Greenfield RS, Flyer DC, Tevethia MJ (1980) SV40 transplantation antigen: relationship to SV40-specific proteins. Cold Spring Harb Symp Quant Biol 44 Pt 1:235–242

    Google Scholar 

  34. Schell TD, Mylin LM, Georgoff I, Teresky AK, Levine AJ, Tevethia SS (1999) Cytotoxic T-lymphocyte epitope immunodominance in the control of choroid plexus tumors in simian virus 40 large T antigen transgenic mice. J Virol 73:5981–5993

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Mylin LM, Schell TD, Roberts D, Epler M, Boesteanu A, Collins EJ, Frelinger JA, Joyce S, Tevethia SS (2000) Quantitation of CD8(+) T-lymphocyte responses to multiple epitopes from simian virus 40 (SV40) large T antigen in C57BL/6 mice immunized with SV40, SV40 T-antigen-transformed cells, or vaccinia virus recombinants expressing full-length T antigen or epitope minigenes. J Virol 74:6922–6934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Asghari F, Fitzner B, Holzhuter SA, Nizze H, de Castro Marques A, Muller S, Moller S, Ibrahim SM, Jaster R (2011) Identification of quantitative trait loci for murine autoimmune pancreatitis. J Med Genet 48:557–562. https://doi.org/10.1136/jmg.2011.089730

    Article  Google Scholar 

  37. Ryschich E, Schmidt J, Hammerling GJ, Klar E, Ganss R (2002) Transformation of the microvascular system during multistage tumorigenesis. Int J Cancer 97:719–725

    Article  Google Scholar 

  38. Zhang B, Karrison T, Rowley DA, Schreiber H (2008) IFN-gamma- and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancers. J Clin Invest 118:1398–1404. https://doi.org/10.1172/JCI33522

    Google Scholar 

  39. Hollenbaugh JA, Dutton RW (2006) IFN-gamma regulates donor CD8 T cell expansion, migration, and leads to apoptosis of cells of a solid tumor. J Immunol 177:3004–3011

    Article  CAS  PubMed  Google Scholar 

  40. Braumuller H, Wieder T, Brenner E, Assmann S, Hahn M, Alkhaled M, Schilbach K, Essmann F, Kneilling M, Griessinger C, Ranta F, Ullrich S, Mocikat R, Braungart K, Mehra T, Fehrenbacher B, Berdel J, Niessner H, Meier F, van den Broek M, Haring HU, Handgretinger R, Quintanilla-Martinez L, Fend F, Pesic M, Bauer J, Zender L, Schaller M, Schulze-Osthoff K, Rocken M (2013) T-helper-1-cell cytokines drive cancer into senescence. Nature 494:361–365. https://doi.org/10.1038/nature11824

    Article  PubMed  Google Scholar 

  41. Matsushita H, Hosoi A, Ueha S, Abe J, Fujieda N, Tomura M, Maekawa R, Matsushima K, Ohara O, Kakimi K (2015) Cytotoxic T lymphocytes block tumor growth both by lytic activity and IFNgamma-dependent cell-cycle arrest. Cancer Immunol Res 3:26–36. https://doi.org/10.1158/2326-6066.CIR-14-0098

    Article  CAS  PubMed  Google Scholar 

  42. Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ (1998) T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393:480–483. https://doi.org/10.1038/31002

    Article  CAS  PubMed  Google Scholar 

  43. Zhang M, Ju W, Yao Z, Yu P, Wei BR, Simpson RM, Waitz R, Fasso M, Allison JP, Waldmann TA (2012) Augmented IL-15Ralpha expression by CD40 activation is critical in synergistic CD8 T cell-mediated antitumor activity of anti-CD40 antibody with IL-15 in TRAMP-C2 tumors in mice. J Immunol 188:6156–6164. https://doi.org/10.4049/jimmunol.1102604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Liu C, Lewis CM, Lou Y, Xu C, Peng W, Yang Y, Gelbard AH, Lizee G, Zhou D, Overwijk WW, Hwu P (2012) Agonistic antibody to CD40 boosts the antitumor activity of adoptively transferred T cells in vivo. J Immunother 35:276–282. https://doi.org/10.1097/CJI.0b013e31824e7f43

    Google Scholar 

  45. Golden EB, Frances D, Pellicciotta I, Demaria S, Helen Barcellos-Hoff M, Formenti SC (2014) Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology 3:e28518. https://doi.org/10.4161/onci.28518

    Article  PubMed  PubMed Central  Google Scholar 

  46. Beatty GL, Torigian DA, Chiorean EG, Saboury B, Brothers A, Alavi A, Troxel AB, Sun W, Teitelbaum UR, Vonderheide RH, O’Dwyer PJ (2013) A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin Cancer Res 19:6286–6295. https://doi.org/10.1158/1078-0432.CCR-13-1320

    Article  CAS  PubMed  Google Scholar 

  47. Dechanet J, Grosset C, Taupin JL, Merville P, Banchereau J, Ripoche J, Moreau JF (1997) CD40 ligand stimulates proinflammatory cytokine production by human endothelial cells. J Immunol 159:5640–5647

    CAS  PubMed  Google Scholar 

  48. Medina-Echeverz J, Ma C, Duffy AG, Eggert T, Hawk N, Kleiner DE, Korangy F, Greten TF (2015) Systemic agonistic anti-CD40 treatment of tumor-bearing mice modulates hepatic myeloid-suppressive cells and causes immune-mediated liver damage. Cancer Immunol Res 3:557–566. https://doi.org/10.1158/2326-6066.CIR-14-0182

    Google Scholar 

  49. Cao ZA, Daniel D, Hanahan D (2002) Sub-lethal radiation enhances anti-tumor immunotherapy in a transgenic mouse model of pancreatic cancer. BMC Cancer 2:11

    Article  PubMed  PubMed Central  Google Scholar 

  50. Byrne KT, Vonderheide RH (2016) CD40 stimulation obviates innate sensors and drives T cell immunity in cancer. Cell Rep 15:2719–2732. https://doi.org/10.1016/j.celrep.2016.05.058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Spranger S, Dai D, Horton B, Gajewski TF (2017) Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 31:711–723e4. https://doi.org/10.1016/j.ccell.2017.04.003

    Article  Google Scholar 

  52. Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, Hwang LN, Yu Z, Wrzesinski C, Heimann DM, Surh CD, Rosenberg SA, Restifo NP (2005) Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8 + T cells. J Exp Med 202:907–912. https://doi.org/10.1084/jem.20050732

    Article  Google Scholar 

  53. Cho BK, Rao VP, Ge Q, Eisen HN, Chen J (2000) Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells. J Exp Med. 192:549–556

    Article  Google Scholar 

  54. Barth RJ Jr, Mule JJ, Spiess PJ, Rosenberg SA (1991) Interferon gamma and tumor necrosis factor have a role in tumor regressions mediated by murine CD8 + tumor-infiltrating lymphocytes. J Exp Med 173:647–658

    Article  Google Scholar 

  55. Chakraborty M, Abrams SI, Coleman CN, Camphausen K, Schlom J, Hodge JW (2004) External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. Cancer Res 64:4328–4337. https://doi.org/10.1158/0008-5472.CAN-04-0073

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Jeremy Haley for outstanding technical assistance and the staff of the Penn State Hershey Flow Cytometry Core Facility for expert assistance.

Funding

This work was supported by Research Grants R01 CA025000 from the National Cancer Institute, National Institutes of Health (to Todd D. Schell) and R01 AI102543 from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (to Aron E. Lukacher). Lindsay K. Ward-Kavanagh and Kathleen M. Kokolus were supported by Training Grant T32 CA060395 from the National Cancer Institute, National Institutes of Health.

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Author notes

  1. Timothy K. Cooper

    Present address: Integrated Research Facility, National Institute of Allergy and Infectious Diseases, Frederick, MD, 21702, USA

  2. Lindsay K. Ward-Kavanagh and Kathleen M. Kokolus contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Microbiology and Immunology, Penn State College of Medicine, 500 University Drive, H107, Hershey, PA, 17033, USA

    Lindsay K. Ward-Kavanagh, Kathleen M. Kokolus, Aron E. Lukacher & Todd D. Schell

  2. Department of Comparative Medicine, Penn State College of Medicine, Hershey, PA, 17033, USA

    Timothy K. Cooper

  3. Department of Pathology, Penn State College of Medicine, Hershey, PA, 17033, USA

    Timothy K. Cooper & Aron E. Lukacher

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  1. Lindsay K. Ward-Kavanagh
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Contributions

Conception and design: Lindsay K. Ward-Kavanagh, Kathleen M. Kokolus, Todd D. Schell. Development of methodology: Lindsay K. Ward-Kavanagh, Timothy K. Cooper, Todd D. Schell. Acquisition of data (performed experiments, provided mice, collected images, etc.): Lindsay K. Ward-Kavanagh, Kathleen M. Kokolus, Aron E. Lukacher, Timothy K. Cooper, Todd D. Schell. Analysis and interpretation of data (computational and statistical analysis): Lindsay K. Ward-Kavanagh, Kathleen M. Kokolus, Todd D. Schell. Writing, review and/or revision of the manuscript: Lindsay K. Ward-Kavanagh, Kathleen M. Kokolus, Aron E. Lukacher, Timothy K. Cooper, Todd D. Schell. Study supervision: Todd D. Schell.

Corresponding author

Correspondence to Todd D. Schell.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All animal studies were approved by the Penn State Hershey Institutional Animal Care and Use Committee (Protocol #47088) and were performed in accordance with recommendations in the Guide for the Care and Use of Laboratory Animals.

Animal source

Mice were bred in specific pathogen-free barrier housing in the Penn State College of Medicine animal vivarium. RT4 mice on the C57BL/6J background were maintained as a homozygous line and bred with C57BL/6J mice to produce hemizygous RT4 mice for experiments. Hemizygous TCR-I mice were bred to homozygous B6.PL-Thy1a/CyJ females (the Jackson Laboratory) to generate CD90.1+ donor T cells. TCR-I mice on the IFNγ-knockout background (TCR-IxGKO) were derived by backcrossing TCR-I mice to homozygous B6.129S7-Ifngtm1Ts/J mice from the Jackson Laboratory.

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Ward-Kavanagh, L.K., Kokolus, K.M., Cooper, T.K. et al. Combined sublethal irradiation and agonist anti-CD40 enhance donor T cell accumulation and control of autochthonous murine pancreatic tumors. Cancer Immunol Immunother 67, 639–652 (2018). https://doi.org/10.1007/s00262-018-2115-2

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