Immunogenic cell death by neoadjuvant oxaliplatin and radiation protects against metastatic failure in high-risk rectal cancer

Simer J Bains, Hanna Abrahamsson, Kjersti Flatmark, Svein Dueland, Knut H Hole, Therese Seierstad, Kathrine Røe Redalen, Sebastian Meltzer, Anne Hansen Ree, Simer J Bains, Hanna Abrahamsson, Kjersti Flatmark, Svein Dueland, Knut H Hole, Therese Seierstad, Kathrine Røe Redalen, Sebastian Meltzer, Anne Hansen Ree

Abstract

Objective: High rates of systemic failure in locally advanced rectal cancer call for a rational use of conventional therapies to foster tumor-defeating immunity.

Methods: We analyzed the high-mobility group box-1 (HMGB1) protein, a measure of immunogenic cell death (ICD), in plasma sampled from 50 patients at the time of diagnosis and following 4 weeks of induction chemotherapy and 5 weeks of sequential chemoradiotherapy, both neoadjuvant modalities containing oxaliplatin. The patients had the residual tumor resected and were followed for long-term outcome.

Results: Patients who met the main study end point-freedom from distant recurrence-showed a significant rise in HMGB1 during the induction chemotherapy and consolidation over the chemoradiotherapy. The higher the ICD increase, the lower was the metastatic failure risk (hazard ratio 0.26, 95% confidence interval 0.11-0.62, P = 0.002). However, patients who received the full-planned oxaliplatin dose of the chemoradiotherapy regimen had poorer metastasis-free survival (P = 0.020) than those who had the oxaliplatin dose reduced to avert breach of the radiation delivery, which is critical to maintain efficient tumor cell kill and in the present case, probably also protected the ongoing radiation-dependent ICD response from systemic oxaliplatin toxicity.

Conclusion: The findings indicated that full-dose induction oxaliplatin followed by an adapted oxaliplatin dose that was compliant with full-intensity radiation caused induction and maintenance of ICD and as a result, durable disease-free outcome for a patient population prone to metastatic progression.

Keywords: Immunogenic cell death; Metastasis; Oxaliplatin; Radiotherapy; Rectal cancer.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Plasma HMGB1 levels during NACT and sequential CRT. The horizontal line in each data cluster represents the median value
Fig. 2
Fig. 2
Plasma HMGB1 profile plots over the course of NACT and sequential CRT for various patient categories. Wild-type or mutant tumor KRAS status (the upper panel). Negative or positive for a DMFS event at study censoring (the middle panel). Negative or positive for an OS event at study censoring. The dashed profile represents cases alive with metastatic disease at censoring (the lower panel). mut mutant, neg negative, pos positive, wt wild-type
Fig. 3
Fig. 3
DMFS for patients receiving the full-planned or reduced oxaliplatin dose during the neoadjuvant CRT

References

    1. Gotwals P, Cameron S, Cipolletta D, Cremasco V, Crystal A, Hewes B, et al. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat Rev Cancer. 2017;17:286–301. doi: 10.1038/nrc.2017.17.
    1. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Ann Rev Immunol. 2013;31:51–72. doi: 10.1146/annurev-immunol-032712-100008.
    1. Tesniere A, Schlemmer F, Boige V, Kepp O, Martins I, Ghiringhelli F, et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene. 2010;29:482–491. doi: 10.1038/onc.2009.356.
    1. Zitvogel L, Kepp O, Senovilla L, Menger L, Chaput N, Kroemer G. Immunogenic tumor cell death for optimal anticancer therapy: the calreticulin exposure pathway. Clin Cancer Res. 2010;16:3100–3104. doi: 10.1158/1078-0432.CCR-09-2891.
    1. Gou HF, Huang J, Shi HS, Chen XC, Wang YS. Chemo-immunotherapy with oxaliplatin and interleukin-7 inhibits colon cancer metastasis in mice. PLoS One. 2014;9:e85789. doi: 10.1371/journal.pone.0085789.
    1. Pol J, Vacchelli E, Aranda F, Castoldi F, Eggermont A, Cremer I, et al. Trial Watch: immunogenic cell death inducers for anticancer chemotherapy. Oncoimmunology. 2015;4:e1008866. doi: 10.1080/2162402X.2015.1008866.
    1. Pfirschke C, Engblom C, Rickelt S, Cortez-Retamozo V, Garris C, Pucci F, et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity. 2016;44:343–354. doi: 10.1016/j.immuni.2015.11.024.
    1. Frey B, Stache C, Rubner Y, Werthmoller N, Schulz K, Sieber R, et al. Combined treatment of human colorectal tumor cell lines with chemotherapeutic agents and ionizing irradiation can in vitro induce tumor cell death forms with immunogenic potential. J Immunotoxicol. 2012;9:301–313. doi: 10.3109/1547691X.2012.693547.
    1. Golden EB, Apetoh L. Radiotherapy and immunogenic cell death. Sem Radiat Oncol. 2015;25:11–17. doi: 10.1016/j.semradonc.
    1. Demaria S, Pilones KA, Vanpouille-Box C, Golden EB, Formenti SC. The optimal partnership of radiation and immunotherapy: from preclinical studies to clinical translation. Radiat Res. 2014;182:170–181. doi: 10.1667/RR13500.1.
    1. Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925–931. doi: 10.1056/NEJMoa1112824.
    1. Whiteside TL, Demaria S, Rodriguez-Ruiz ME, Zarour HM, Melero I. Emerging opportunities and challenges in cancer immunotherapy. Clin Cancer Res. 2016;22:1845–1855. doi: 10.1158/1078-0432.CCR-16-0049.
    1. Aklilu M, Eng C. The current landscape of locally advanced rectal cancer. Nat Rev Clin Oncol. 2011;8:649–659. doi: 10.1038/nrclinonc.
    1. Gerard JP, Azria D, Gourgou-Bourgade S, Martel-Lafay I, Hennequin C, Etienne PL, et al. Clinical outcome of the ACCORD 12/0405 PRODIGE 2 randomized trial in rectal cancer. J Clin Oncol. 2012;30:4558–4565. doi: 10.1200/JCO.2012.42.8771.
    1. Bosset JF, Calais G, Mineur L, Maingon P, Stojanovic-Rundic S, Bensadoun RJ, et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol. 2014;15:184–190. doi: 10.1016/S1470-2045(13)70599-0.
    1. Rodel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, et al. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015;16:979–989. doi: 10.1016/S1470-2045(15)00159-X.
    1. Breugom AJ, Swets M, Bosset JF, Collette L, Sainato A, Cionini L, et al. Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol. 2015;16:200–207. doi: 10.1016/S1470-2045(14)71199-4.
    1. Calvo FA, Serrano FJ, Diaz-Gonzalez JA, Gomez-Espi M, Lozano E, Garcia R, et al. Improved incidence of pT0 downstaged surgical specimens in locally advanced rectal cancer (LARC) treated with induction oxaliplatin plus 5-fluorouracil and preoperative chemoradiation. Ann Oncol. 2006;17:1103–1110. doi: 10.1093/annonc/mdl085.
    1. Chau I, Brown G, Cunningham D, Tait D, Wotherspoon A, Norman AR, et al. Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer. J Clin Oncol. 2006;24:668–674. doi: 10.1200/JCO.2005.04.4875.
    1. Koeberle D, Burkhard R, von Moos R, Winterhalder R, Hess V, Heitzmann F, et al. Phase II study of capecitabine and oxaliplatin given prior to and concurrently with preoperative pelvic radiotherapy in patients with locally advanced rectal cancer. Br J Cancer. 2008;98:1204–1209. doi: 10.1038/sj.bjc.6604297.
    1. Chua YJ, Barbachano Y, Cunningham D, Oates JR, Brown G, Wotherspoon A, et al. Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial. Lancet Oncol. 2010;11:241–248. doi: 10.1016/S1470-2045(09)70381-X.
    1. Schou JV, Larsen FO, Rasch L, Linnemann D, Langhoff J, Hogdall E, et al. Induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiotherapy before total mesorectal excision in patients with locally advanced rectal cancer. Ann Oncol. 2012;23:2627–2633. doi: 10.1093/annonc/mds056.
    1. Dewdney A, Cunningham D, Tabernero J, Capdevila J, Glimelius B, Cervantes A, et al. Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C) J Clin Oncol. 2012;30:1620–1627. doi: 10.1200/JCO.2011.39.6036.
    1. Nilsson PJ, van Etten B, Hospers GA, Pahlman L, van de Velde CJ, Beets-Tan RG, et al. Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer–the RAPIDO trial. BMC Cancer. 2013;13:279. doi: 10.1186/1471-2407-13-279.
    1. Dueland S, Ree AH, Groholt KK, Saelen MG, Folkvord S, Hole KH, et al. Oxaliplatin-containing preoperative therapy in locally advanced rectal cancer: local response, toxicity and long-term outcome. Clin Oncol (R Coll Radiol) 2016;28:532–539. doi: 10.1016/j.clon.2016.01.014.
    1. Meltzer S, Kalanxhi E, Hektoen HH, Dueland S, Flatmark K, Redalen KR, et al. Systemic release of osteoprotegerin during oxaliplatin-containing induction chemotherapy and favorable systemic outcome of sequential radiotherapy in rectal cancer. Oncotarget. 2016;7:34907–34917. doi: 10.18632/oncotarget.8995.
    1. Kalanxhi E, Meltzer S, Schou JV, Larsen FO, Dueland S, Flatmark K, et al. Systemic immune response induced by oxaliplatin-based neoadjuvant therapy favours survival without metastatic progression in high-risk rectal cancer. Br J Cancer. 2018;118:1322–1328. doi: 10.1038/s41416-018-0085-y.
    1. Ree AH, Kristensen AT, Saelen MG, de Wijn R, Edvardsen H, Jovanovic J, et al. Tumor phosphatidylinositol-3-kinase signaling and development of metastatic disease in locally advanced rectal cancer. PLoS ONE. 2012;7:e50806. doi: 10.1371/journal.pone.0050806.
    1. Seierstad T, Hole KH, Groholt KK, Dueland S, Ree AH, Flatmark K, et al. MRI volumetry for prediction of tumour response to neoadjuvant chemotherapy followed by chemoradiotherapy in locally advanced rectal cancer. Br J Radiol. 2015;88:20150097. doi: 10.1259/bjr.20150097.
    1. Lal N, White BS, Goussous G, Pickles O, Mason MJ, Beggs AD, et al. KRAS mutation and consensus molecular subtypes 2 and 3 are independently associated with reduced immune infiltration and reactivity in colorectal cancer. Clin Cancer Res. 2018;24:224–233. doi: 10.1158/1078-0432.CCR-17-1090.
    1. Liao W, Overman MJ, Boutin AT, Shang X, Zhao D, Dey P, et al. KRAS-IRF2 axis drives immune suppression and immune therapy resistance in colorectal cancer. Cancer Cell. 2019;35:559–572.e7. doi: 10.1016/j.ccell.2019.02.008.
    1. Fang H, Ang B, Xu X, Huang X, Wu Y, Sun Y, et al. TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells. Cell Mol Immunol. 2014;11:150–159. doi: 10.1038/cmi.2013.59.
    1. Hato SV, Khong A, de Vries IJ, Lesterhuis WJ. Molecular pathways: the immunogenic effects of platinum-based chemotherapeutics. Clin Cancer Res. 2014;20:2831–2837. doi: 10.1158/1078-0432.CCR-13-3141.
    1. Nash GM, Gimbel M, Shia J, Nathanson DR, Ndubuisi MI, Zeng ZS, et al. KRAS mutation correlates with accelerated metastatic progression in patients with colorectal liver metastases. Ann Surg Oncol. 2010;17:572–578. doi: 10.1245/s10434-009-0605-3.
    1. Duldulao MP, Lee W, Nelson RA, Li W, Chen Z, Kim J, et al. Mutations in specific codons of the KRAS oncogene are associated with variable resistance to neoadjuvant chemoradiation therapy in patients with rectal adenocarcinoma. Ann Surg Oncol. 2013;20:2166–2171. doi: 10.1245/s10434-013-2910-0.
    1. Chow OS, Kuk D, Keskin M, Smith JJ, Camacho N, Pelossof R, et al. KRAS and combined KRAS/TP53 mutations in locally advanced rectal cancer are independently associated with decreased response to neoadjuvant therapy. Ann Surg Oncol. 2016;23:2548–2555. doi: 10.1245/s10434-016-5205-4.
    1. Vatner RE, Cooper BT, Vanpouille-Box C, Demaria S, Formenti SC. Combinations of immunotherapy and radiation in cancer therapy. Front Oncol. 2014;4:325. doi: 10.3389/fonc.2014.00325.
    1. Gerard JP, Chamorey E, Gourgou-Bourgade S, Benezery K, de Laroche G, Mahé MA, et al. Clinical response (cCR) after neoadjuvant chemoradiotherapy and conservative treatment in rectal cancer. Findings from the ACCORD 12/PRODIGE 2 randomized trial. Radiother Oncol. 2015;115:246–252. doi: 10.1016/j.radonc.2015.04.003.
    1. Ascele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, et al. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol. 2011;29:2773–2780. doi: 10.1200/JCO.2010.34.4911.
    1. O’Connell MJ, Colangelo LH, Beart RW, Petrelli NJ, Allegra CJ, Sharif S, et al. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from national surgical adjuvant breast and bowel project trial R-04. J Clin Oncol. 2014;32:1927–1934. doi: 10.1200/JCO.2013.53.7753.
    1. Merad M, Sathe P, Helft J, Miller J, Mortha A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Ann Rev Immunol. 2013;31:563–604. doi: 10.1146/annurev-immunol-020711-074950.
    1. Aymeric L, Apetoh L, Ghiringhelli F, Tesniere A, Martins I, Kroemer G, et al. Tumor cell death and ATP release prime dendritic cells and efficient anticancer immunity. Cancer Res. 2010;70:855–858. doi: 10.1158/0008-5472.CAN-09-3566.
    1. Ahn J, Xia T, Rabasa Capote A, Betancourt D, Barber GN. Extrinsic phagocyte-dependent STING signaling dictates the immunogenicity of dying cells. Cancer Cell. 2018;33:862–873. doi: 10.1016/j.ccell.2018.03.027.
    1. Harding SM, Benci JL, Irianto J, Discher DE, Minn AJ, Greenberg RA. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature. 2017;548:466–470. doi: 10.1038/nature23470.
    1. Vanpouille-Box C, Alard A, Aryankalayil MJ, Sarfraz Y, Diamond JM, Schneider RJ, et al. DNA exonuclease Trax1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun. 2017;8:15618. doi: 10.1038/ncomms15618.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する