CD4 T cells target colorectal cancer antigens upregulated by oxaliplatin
Jeanne Galaine
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Search for more papers by this authorCélia Turco
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
University Hospital of Besançon, Department of Gastrointestinal Surgery, Besançon, France
Search for more papers by this authorCharline Vauchy
INSERM CIC-1431, University Hospital of Besançon, Clinical Investigation Center un Biotherapy, Fédération Hospitalo-Universitaire INCREASE, LabEx LipSTIC, Besançon, France
Search for more papers by this authorBernard Royer
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
University Hospital of Besançon, Department of pharmacotoxicology, Besançon, France
Search for more papers by this authorPatricia Mercier-Letondal
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Search for more papers by this authorLise Queiroz
INSERM CIC-1431, University Hospital of Besançon, Clinical Investigation Center un Biotherapy, Fédération Hospitalo-Universitaire INCREASE, LabEx LipSTIC, Besançon, France
Search for more papers by this authorRomain Loyon
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Search for more papers by this authorVirginie Mouget
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Search for more papers by this authorRomain Boidot
Centre Georges-François Leclerc, Platform for Transfer to Cancer Biology, Dijon, France
Search for more papers by this authorCaroline Laheurte
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
EFS Bourgogne Franche-Comté, INSERM CIC-1431, CHRU Besançon, Plateforme de BioMonitoring, Besançon, France
Search for more papers by this authorZaher Lakkis
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
University Hospital of Besançon, Department of Gastrointestinal Surgery, Besançon, France
Search for more papers by this authorMarine Jary
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
University Hospital of Besançon, Department of Medical Oncology, Besançon, France
Search for more papers by this authorOlivier Adotévi
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
University Hospital of Besançon, Department of Medical Oncology, Besançon, France
Search for more papers by this authorChristophe Borg
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
University Hospital of Besançon, Department of Medical Oncology, Besançon, France
Search for more papers by this authorCorresponding Author
Yann Godet
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Correspondence to: Yann Godet, Univ. Bourgogne Franche-Comté, 8, rue du Docteur Jean-François-Xavier Girod, BP 1937, 25020 Besançon Cedex, France, Tel.: 33-3-81-61-56-15, Fax: 33-3-81-66-97-08, E-mail: [email protected]Search for more papers by this authorJeanne Galaine
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Search for more papers by this authorCélia Turco
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
University Hospital of Besançon, Department of Gastrointestinal Surgery, Besançon, France
Search for more papers by this authorCharline Vauchy
INSERM CIC-1431, University Hospital of Besançon, Clinical Investigation Center un Biotherapy, Fédération Hospitalo-Universitaire INCREASE, LabEx LipSTIC, Besançon, France
Search for more papers by this authorBernard Royer
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
University Hospital of Besançon, Department of pharmacotoxicology, Besançon, France
Search for more papers by this authorPatricia Mercier-Letondal
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Search for more papers by this authorLise Queiroz
INSERM CIC-1431, University Hospital of Besançon, Clinical Investigation Center un Biotherapy, Fédération Hospitalo-Universitaire INCREASE, LabEx LipSTIC, Besançon, France
Search for more papers by this authorRomain Loyon
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Search for more papers by this authorVirginie Mouget
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Search for more papers by this authorRomain Boidot
Centre Georges-François Leclerc, Platform for Transfer to Cancer Biology, Dijon, France
Search for more papers by this authorCaroline Laheurte
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
EFS Bourgogne Franche-Comté, INSERM CIC-1431, CHRU Besançon, Plateforme de BioMonitoring, Besançon, France
Search for more papers by this authorZaher Lakkis
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
University Hospital of Besançon, Department of Gastrointestinal Surgery, Besançon, France
Search for more papers by this authorMarine Jary
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
University Hospital of Besançon, Department of Medical Oncology, Besançon, France
Search for more papers by this authorOlivier Adotévi
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
University Hospital of Besançon, Department of Medical Oncology, Besançon, France
Search for more papers by this authorChristophe Borg
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
University Hospital of Besançon, Department of Medical Oncology, Besançon, France
Search for more papers by this authorCorresponding Author
Yann Godet
Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
Correspondence to: Yann Godet, Univ. Bourgogne Franche-Comté, 8, rue du Docteur Jean-François-Xavier Girod, BP 1937, 25020 Besançon Cedex, France, Tel.: 33-3-81-61-56-15, Fax: 33-3-81-66-97-08, E-mail: [email protected]Search for more papers by this authorAbstract
Immune checkpoint blockade has proven its efficacy in hypermutated subtypes of metastatic colorectal cancers (mCRC). Immunogenic potential can also be observed with conventional chemotherapies, but this property has never been explored thoroughly in CRC patients. The CRC therapeutic arsenal includes oxaliplatin, a well-characterized platinum drug already described as immunogenic. Here, we investigated the impact of the oxaliplatin-based treatment on mCRC immunopeptidome. We demonstrated that oxaliplatin-resistant CRC cell lines overexpressed telomerase reverse transcriptase (TERT), colorectal-associated-tumor antigen-1 (COA-1) and mesothelin tumor-associated antigens. We identified new HLA class-II-restricted and promiscuous peptides derived from COA-1 and mesothelin. The two naturally processed peptides COA-1331-345 and Meso366-380 appear to be the most immunogenic in mCRC patients. A prospective cohort of 162 mCRC patients enabled us to explore the impact of oxaliplatin exposure on the antitumor-specific immune response. Interestingly, chemotherapy-naive mCRC patients present high immune CD4 T-cell responses directed against TERT, COA-1 and mesothelin-derived peptides. These antitumor T-cell responses were maintained after 3 months of oxaliplatin-based treatment. Altogether, these findings highlight the interest of immunostimulatory agents to improve the management of chemoresistant mCRC patients. Finally, the high frequency of immune responses targeting the new immunogenic peptides derived from COA-1 and mesothelin support their use in immunomonitoring strategies.
Abstract
What's new?
Oxaliplatin, like other platinum drugs, kills cancer cells through induction of DNA damage, but immunomodulatory properties have also been described. Here the authors examined the immunopeptidome in oxaliplatin-resistant colon cancer cell lines. They identified novel MHC class II-restricted peptides derived from overexpressed tumor antigens and show that these are immunogenic in metastatic colorectal cancer patients treated with oxaliplatin. These findings may lead to new immunotherapeutic approaches to oxaliplatin-resistant colon cancer.
Supporting Information
| Filename | Description |
|---|---|
| ijc32620-sup-0001-FigureS1.TIFTIFF image, 4.1 MB | Figure S1 Detection of spontaneous HLA-DR-restricted COA-1 and mesothelin-specific T cell responses in healthy donors. PBMC from 15 healthy donors were stimulated with a mixture of 3 COA-1 peptides (COA-172-86, COA-1331-345, COA-1445-459) and 2 mesothelin peptides (Meso366-380 and Meso523-537) at 5 μg/ml during ten days. The T cells reactivity against the individual peptide was detected by IFN-γ ELISpot assay as described in material and methods. Results are shown as median of ΔIFN-γ spots number (magnitude) and frequency. Stimulation with CEF peptide was used as control of T cell reactivity. All the experiments were conducted in duplicates. |
| ijc32620-sup-0002-FigureS2.tifTIFF image, 57.1 KB | Figure S2 Phenotypic characterization of EKF and ESV-specific CD4 T cell clones. Polarization of resting EKF and ESV-specific CD4 T cells clones were determined by analyzing CXCR3, CCR4, CCR6 and CRTH2 expression by flow cytometry. |
| ijc32620-sup-0003-FigureS3.tifTIFF image, 348.6 KB | Figure S3 Analysis of HLA-DR-restricted TERT, COA-1 and mesothelin-specific immune responses intensity in chemotherapy-naive mCRC immune responders. PBMC from chemotherapy-naive mCRC patients were cultured either with a mixture of 3 COA-1 peptides (COA-172-86, COA-1331-345, COA-1445-459) and 2 mesothelin peptides (Meso366-380 and Meso523-537), or 8 TERT peptides (UCP1, UCP2, UCP3, UCP4, TERT541-555, TERT573-587, TERT613-627, TERT911-925) at 5 μg/ml. After a short-term culture, the T cells reactivity against the individual peptide was detected by IFN-γ ELISpot assay as described in material and methods. Stimulation with CEF peptide was used as control of T cell reactivity. Results are presented as a ratio among immune responders calculated as followed: calculated ratio = [(number of spots observed in peptide conditions) - (number of spots observed in the control medium conditions)]/(number of spots observed in the medium conditions). All the experiments were conducted in duplicates. |
| ijc32620-sup-0004-FigureS4.tifTIFF image, 68.8 KB | Figure S4 Analysis of HLA-DR-restricted T cell responses against TERT, COA-1 and mesothelin peptides before and after oxaliplatin exposure in mCRC immune responders. PBMC were cultured either with a mixture of 3 COA-1 peptides (COA-172-86, COA-1331-345, COA-1445-459) and 2 mesothelin peptides (Meso366-380, Meso523-537), or 8 TERT peptides (UCP1, UCP2, UCP3, UCP4, TERT541-555, TERT573-587, TERT613-627, TERT911-925). The presence of antigen-specific T cells was detected after a short-term culture using IFN-γ ELISPOT assay. Magnitude of spontaneous T cell responses against TERT, COA-1, mesothelin or CEF peptides before (T0) and 3 months (T3) after the end of oxaliplatin-based chemotherapy in mCRC patients. Results are presented as a ratio among immune responders calculated as followed: calculated ratio = [(number of spots observed in peptide conditions) - (number of spots observed in the control medium conditions)]/(number of spots observed in the medium conditions). Stimulation with CEF peptide was used as control of T cell reactivity. All the experiments were conducted in duplicates. |
| ijc32620-sup-0005-Supinfo1.tifTIFF image, 132.6 KB | Appendix S1: Supporting Information1 |
| ijc32620-sup-0006-Supinfo2.TIFTIFF image, 756.9 KB | Appendix S1: Supporting Information2 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Binefa G, Rodríguez-Moranta F, Teule A, et al. Colorectal cancer: from prevention to personalized medicine. World J Gastroenterol 2014; 20: 6786–808.
- 2Baba K, Oshita A, Kohyama M, et al. Successful treatment of conversion chemotherapy for initially unresectable synchronous colorectal liver metastasis. World J Gastroenterol 2015; 21: 1982–8.
- 3Park M-S, Yi N-J, Son S-Y, et al. Histopathologic factors affecting tumor recurrence after hepatic resection in colorectal liver metastases. Ann Surg Treat Res 2014; 87: 14–21.
- 4André T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009; 27: 3109–16.
- 5de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 2938–47.
- 6Fink D, Zheng H, Nebel S, et al. In vitro and in vivo resistance to cisplatin in cells that have lost DNA mismatch repair. Cancer Res 1997; 57: 1841–5.
- 7Lintoiu-Ursut B, Tulin A, Constantinoiu S. Recurrence after hepatic resection in colorectal cancer liver metastasis—review article. J Med Life 2015; 8: 12–4.
- 8Martinez-Balibrea E, Martínez-Cardús A, Ginés A, et al. Tumor-related molecular mechanisms of oxaliplatin resistance. Mol Cancer Ther 2015; 14: 1767–76.
- 9Tosolini M, Kirilovsky A, Mlecnik B, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res 2011; 71: 1263–71.
- 10Fridman WH, Pagès F, Sautès-Fridman C, et al. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 2012; 12: 298–306.
- 11Borst J, Ahrends T, Bąbała N, et al. CD4 + T cell help in cancer immunology and immunotherapy. Nat Rev Immunol 2018; 18: 635–47.
- 12Kennedy R, Celis E. Multiple roles for CD4+ T cells in anti-tumor immune responses. Immunol Rev 2008; 222: 129–44.
- 13Spitzer MH, Carmi Y, Reticker-Flynn NE, et al. Systemic immunity is required for effective cancer immunotherapy. Cell 2017; 168: 487–502.e15.
- 14Zanetti M. Tapping CD4 T cells for cancer immunotherapy: the choice of personalized genomics. J Immunol 2015; 194: 2049–56.
- 15Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair deficient/microsatellite instability–high colorectal cancer (CheckMate 142): results of an open-label, multicentre, phase 2 study. Lancet Oncol 2017; 18: 1182–91.
- 16Pagès F, Mlecnik B, Marliot F, et al. International validation of the consensus immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 2018; 391: 2128–39.
- 17Koopman M, Kortman GA, Mekenkamp L, et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer 2009; 100: 266–73.
- 18Zitvogel L, Galluzzi L, Smyth MJ, et al. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 2013; 39: 74–88.
- 19Hato SV, Khong A, de Vries IJM, et al. Molecular pathways: the immunogenic effects of platinum-based chemotherapeutics. Clin Cancer Res 2014; 20: 2831–7.
- 20Lesterhuis WJ, Punt CJA, Hato SV, et al. Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice. J Clin Invest 2011; 121: 3100–8.
- 21Prete SP, Turriziani M, Massara MC, et al. Combined effects of 5-fluorouracil, folinic acid and oxaliplatin on the expression of carcinoembryonic antigen in human colon cancer cells: pharmacological basis to develop an active antitumor immunochemotherapy. J Exp Clin Cancer Res 2008; 27: 5.
- 22Godet Y, Fabre E, Dosset M, et al. Analysis of spontaneous tumor-specific CD4 T-cell immunity in lung cancer using promiscuous HLA-DR telomerase-derived epitopes: potential synergistic effect with chemotherapy response. Clin Cancer Res 2012; 18: 2943–53.
- 23Laheurte C, Galaine J, Beziaud L, et al. Immunoprevalence and magnitude of HLA-DP4 versus HLA-DR-restricted spontaneous CD4+ Th1 responses against telomerase in cancer patients. Oncoimmunology 2015; 5:e1137416.
- 24Dosset M, Godet Y, Vauchy C, et al. Universal cancer peptide-based therapeutic vaccine breaks tolerance against telomerase and eradicates established tumor. Clin Cancer Res 2012; 18: 6284–95.
- 25Galaine J, Kellermann G, Guillaume Y, et al. Heparan sulfate proteoglycans promote telomerase internalization and MHC class II presentation on dendritic cells. J Immunol 2016; 197: 1597–608.
- 26Por E, Byun H-J, Lee E-J, et al. The cancer/testis antigen CAGE with oncogenic potential stimulates cell proliferation by up-regulating cyclins D1 and E in an AP-1- and E2F-dependent manner. J Biol Chem 2010; 285: 14475–85.
- 27Wang P, Sidney J, Dow C, et al. A systematic assessment of MHC class II peptide binding predictions and evaluation of a consensus approach. PLoS Comput Biol 2008; 4:e1000048.
- 28Wang P, Sidney J, Kim Y, et al. Peptide binding predictions for HLA DR, DP and DQ molecules. BMC Bioinformatics 2010; 11: 568.
- 29Paul S, Lindestam Arlehamn CS, Scriba TJ, et al. Development and validation of a broad scheme for prediction of HLA class II restricted T cell epitopes. J Immunol Methods 2015; 422: 28–34.
- 30Maccalli C, Cristanziano VD, Fodale V, et al. Induction of both CD8+ and CD4+ T-cell–mediated responses in colorectal cancer patients by colon antigen-1. Clin Cancer Res 2008; 14: 7292–303.
- 31Bobinet M, Vignard V, Rogel A, et al. MELOE-1 antigen contains multiple HLA class II T cell epitopes recognized by Th1 CD4+ T cells from melanoma patients. PLoS One 2012; 7:e51716.
- 32Galluzzi L, Buqué A, Kepp O, et al. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 2015; 28: 690–714.
- 33West NR, McCuaig S, Franchini F, et al. Emerging cytokine networks in colorectal cancer. Nat Rev Immunol 2015; 15: 615–29.
- 34Obeid M, Tesniere A, Ghiringhelli F, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 2007; 13: 54–61.
- 35Ramakrishnan R, Assudani D, Nagaraj S, et al. Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. J Clin Invest 2010; 120: 1111–24.
- 36Liu WM, Fowler DW, Smith P, et al. Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br J Cancer 2010; 102: 115–23.
- 37Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 2007; 13: 1050–9.
- 38Rubinfeld B, Upadhyay A, Clark SL, et al. Identification and immunotherapeutic targeting of antigens induced by chemotherapy. Nat Biotechnol 2006; 24: 205–9.
- 39Whiteside MA, Chen D-T, Desmond RA, et al. A novel time-course cDNA microarray analysis method identifies genes associated with the development of cisplatin resistance. Oncogene 2004; 23: 744–52.
- 40Li X-X, Peng J-J, Liang L, et al. RNA-seq identifies determinants of oxaliplatin sensitivity in colorectal cancer cell lines. Int J Clin Exp Pathol 2014; 7: 3763–70.
- 41Wong P-P, Yeoh CC, Ahmad AS, et al. Identification of MAGEA antigens as causal players in the development of tamoxifen-resistant breast cancer. Oncogene 2014; 33: 4579–88.
- 42Kang K-W, Lee M-J, Song J-A, et al. Overexpression of goosecoid homeobox is associated with chemoresistance and poor prognosis in ovarian carcinoma. Oncol Rep 2014; 32: 189–98.
- 43Cheng W-F, Huang C-Y, Chang M-C, et al. High mesothelin correlates with chemoresistance and poor survival in epithelial ovarian carcinoma. Br J Cancer 2009; 100: 1144–53.
- 44Chen Y, Ayaru L, Mathew S, et al. Expansion of anti-mesothelin specific CD4+ and CD8+ T cell responses in patients with pancreatic carcinoma. PLoS One 2014; 9:e88133.
- 45Chevalier MF, Bobisse S, Costa-Nunes C, et al. High-throughput monitoring of human tumor-specific T-cell responses with large peptide pools. Oncoimmunology 2015; 4:e1029702.
- 46Vincent J, Mignot G, Chalmin F, et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 2010; 70: 3052–61.
- 47Lesterhuis WJ, de Vries IJM, Aarntzen EA, et al. A pilot study on the immunogenicity of dendritic cell vaccination during adjuvant oxaliplatin/capecitabine chemotherapy in colon cancer patients. Br J Cancer 2010; 103: 1415–21.
- 48Rivera Vargas T, Humblin E, Végran F, et al. TH9 cells in anti-tumor immunity. Semin Immunopathol 2017; 39: 39–46.
- 49Bergmann-Leitner ES, Abrams SI. Treatment of human colon carcinoma cell lines with anti-neoplastic agents enhances their lytic sensitivity to antigen-specific CD8+ cytotoxic T lymphocytes. Cancer Immunol Immunother 2001; 50: 445–55.
- 50Pfirschke C, Engblom C, Rickelt S, et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity 2016; 44: 343–54.
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