Top

Published in:

01-12-2021 | Melanoma | Research

Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade

Authors: Chi Yan, Nabil Saleh, Jinming Yang, Caroline A. Nebhan, Anna E. Vilgelm, E. Premkumar Reddy, Joseph T. Roland, Douglas B. Johnson, Sheau-Chiann Chen, Rebecca L. Shattuck-Brandt, Gregory D. Ayers, Ann Richmond

Published in: Molecular Cancer | Issue 1/2021

Abstract

Background

While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy.

Methods

Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic. RGS monotherapy or in combination therapy with ICB were investigated using immunocompetent mouse models of BRAF^wt and BRAF^mut melanoma and analyzed in reference to patient data.

Results

RGS treatment (300 mg/kg) was well tolerated in mice and resulted in ~ 50% inhibition of tumor growth as monotherapy and ~ 70% inhibition in combination with αPD1 + αCTLA4. RGS-induced tumor growth inhibition depends on CD40 upregulation in melanoma cells followed by immunogenic cell death, leading to enriched dendritic cells and activated T cells in the tumor microenvironment. The RGS-initiated tumor suppression was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8⁺ cytotoxic T cells. Treatment with either dabrafenib and trametinib or with RGS, increased CD40⁺SOX10⁺ melanoma cells in the tumors of melanoma patients and patient-derived xenografts. High CD40 expression level correlates with beneficial T-cell responses and better survival in a TCGA dataset from melanoma patients. Expression of CD40 by melanoma cells is associated with therapeutic response to RAF/MEK inhibition and ICB.

Conclusions

Our data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + ICB for melanoma patients who do not respond to ICB alone.

Trial registration

NCT01205815 (Sept 17, 2010).

Graphical abstract

Available only for authorised users

Reddy BY, Miller DM, Tsao H. Somatic driver mutations in melanoma. Cancer. 2017;123(S11):2104–17. https://doi.org/10.1002/cncr.30593.CrossRefPubMed

Millis SZ, Ikeda S, Reddy S, Gatalica Z, Kurzrock R. Landscape of phosphatidylinositol-3-kinase pathway alterations across 19784 diverse solid tumors. JAMA Oncol. 2016;2(12):1565–73. https://doi.org/10.1001/jamaoncol.2016.0891.CrossRefPubMed

Long GV, Hauschild A, Santinami M, Atkinson V, Mandala M, Chiarion-Sileni V, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377(19):1813–23. https://doi.org/10.1056/NEJMoa1708539.CrossRefPubMed

Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867–76. https://doi.org/10.1056/NEJMoa1408868.CrossRefPubMed

Charles J, Martel C, de Fraipont F, Leccia MT, Robert C, Busser B. Mechanisms of resistance to anti-BRAF treatments. Ann Dermatol Venereol. 2014;141(11):671–81. https://doi.org/10.1016/j.annder.2014.06.021.CrossRefPubMed

Hernandez-Davies JE, Tran TQ, Reid MA, Rosales KR, Lowman XH, Pan M, et al. Vemurafenib resistance reprograms melanoma cells towards glutamine dependence. J Transl Med. 2015;13(1):210. https://doi.org/10.1186/s12967-015-0581-2.CrossRefPubMedPubMedCentral

Manzano JL, Layos L, Buges C, de Los Llanos Gil M, Vila L, Martinez-Balibrea E, et al. Resistant mechanisms to BRAF inhibitors in melanoma. Ann Transl Med. 2016;4:237.CrossRefPubMedPubMedCentral

Wolchok J. How recent advances in immunotherapy are changing the standard of care for patients with metastatic melanoma. Ann Oncol. 2012;23(Suppl 8):viii15–21.CrossRefPubMedPubMedCentral

Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. https://doi.org/10.1056/NEJMoa1003466.CrossRefPubMedPubMedCentral

10.

Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381(16):1535–46. https://doi.org/10.1056/NEJMoa1910836.CrossRefPubMed

11.

Marin-Acevedo JA, Chirila RM, Dronca RS. Immune checkpoint inhibitor toxicities. Mayo Clin Proc. 2019;94(7):1321–9. https://doi.org/10.1016/j.mayocp.2019.03.012.CrossRefPubMed

12.

Dummer R, Schadendorf D, Ascierto PA, Arance A, Dutriaux C, Di Giacomo AM, et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(4):435–45. https://doi.org/10.1016/S1470-2045(17)30180-8.CrossRefPubMed

13.

Greger JG, Eastman SD, Zhang V, Bleam MR, Hughes AM, Smitheman KN, et al. Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol Cancer Ther. 2012;11(4):909–20. https://doi.org/10.1158/1535-7163.MCT-11-0989.CrossRefPubMed

14.

Sosman JAKM, Lolkema MPJ, et al. A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: early encouraging clinical activity. J Clin Oncol. 2014;32(15_suppl):9009. https://doi.org/10.1200/jco.2014.32.15_suppl.9009.CrossRef

15.

Xu F, He Q, Li X, Chang CK, Wu LY, Zhang Z, et al. Rigosertib as a selective anti-tumor agent can ameliorate multiple dysregulated signaling transduction pathways in high-grade myelodysplastic syndrome. Sci Rep. 2014;4:7310.CrossRefPubMedPubMedCentral

16.

Hyoda T, Tsujioka T, Nakahara T, Suemori S, Okamoto S, Kataoka M, et al. Rigosertib induces cell death of a myelodysplastic syndrome-derived cell line by DNA damage-induced G2/M arrest. Cancer Sci. 2015;106(3):287–93. https://doi.org/10.1111/cas.12605.CrossRefPubMedPubMedCentral

17.

Chapman CM, Sun X, Roschewski M, Aue G, Farooqui M, Stennett L, et al. ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012;18(7):1979–91. https://doi.org/10.1158/1078-0432.CCR-11-2113.CrossRefPubMedPubMedCentral

18.

Athuluri-Divakar SK, Vasquez-Del Carpio R, Dutta K, Baker SJ, Cosenza SC, Basu I, et al. A small molecule RAS-mimetic disrupts RAS association with effector proteins to block signaling. Cell. 2016;165(3):643–55. https://doi.org/10.1016/j.cell.2016.03.045.CrossRefPubMedPubMedCentral

19.

Prasad A, Khudaynazar N, Tantravahi RV, Gillum AM, Hoffman BS. ON 01910.Na (rigosertib) inhibits PI3K/Akt pathway and activates oxidative stress signals in head and neck cancer cell lines. Oncotarget. 2016;7(48):79388–400. https://doi.org/10.18632/oncotarget.12692.CrossRefPubMedPubMedCentral

20.

Dai YH, Hung LY, Chen RY, Lai CH, Chang KC. ON 01910.Na inhibits growth of diffuse large B-cell lymphoma by cytoplasmic sequestration of sumoylated C-MYB/TRAF6 complex. Transl Res. 2016;175:129–43 e113. https://doi.org/10.1016/j.trsl.2016.04.001.CrossRefPubMed

21.

Garcia-Manero G, Fenaux P, Al-Kali A, Baer MR, Sekeres MA, Roboz GJ, et al. Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial. Lancet Oncol. 2016;17(4):496–508. https://doi.org/10.1016/S1470-2045(16)00009-7.CrossRefPubMed

22.

Silverman LR, Greenberg P, Raza A, Olnes MJ, Holland JF, Reddy P, et al. Clinical activity and safety of the dual pathway inhibitor rigosertib for higher risk myelodysplastic syndromes following DNA methyltransferase inhibitor therapy. Hematol Oncol. 2015;33(2):57–66. https://doi.org/10.1002/hon.2137.CrossRefPubMed

23.

Jimeno A, Li J, Messersmith WA, Laheru D, Rudek MA, Maniar M, et al. Phase I study of ON 01910.Na, a novel modulator of the polo-like kinase 1 pathway, in adult patients with solid tumors. J Clin Oncol. 2008;26(34):5504–10. https://doi.org/10.1200/JCO.2008.17.9788.CrossRefPubMedPubMedCentral

24.

O'Neil BH, Scott AJ, Ma WW, Cohen SJ, Leichman L, Aisner DL, et al. A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer. Ann Oncol. 2015;26(12):2505. https://doi.org/10.1093/annonc/mdv477.CrossRefPubMedPubMedCentral

25.

Ohnuma T, Lehrer D, Ren C, Cho SY, Maniar M, Silverman L, et al. Phase 1 study of intravenous rigosertib (ON 01910.Na), a novel benzyl styryl sulfone structure producing G2/M arrest and apoptosis, in adult patients with advanced cancer. Am J Cancer Res. 2013;3(3):323–38.PubMedPubMedCentral

26.

Tong AW, Stone MJ. Prospects for CD40-directed experimental therapy of human cancer. Cancer Gene Ther. 2003;10(1):1–13. https://doi.org/10.1038/sj.cgt.7700527.CrossRefPubMed

27.

Kalbasi A, Fonsatti E, Natali PG, Altomonte M, Bertocci E, Cutaia O, et al. CD40 expression by human melanocytic lesions and melanoma cell lines and direct CD40 targeting with the therapeutic anti-CD40 antibody CP-870,893. J Immunother. 2010;33(8):810–6. https://doi.org/10.1097/CJI.0b013e3181ee73a7.CrossRefPubMed

28.

von Leoprechting A, van der Bruggen P, Pahl HL, Aruffo A, Simon JC. Stimulation of CD40 on immunogenic human malignant melanomas augments their cytotoxic T lymphocyte-mediated lysis and induces apoptosis. Cancer Res. 1999;59:1287–94.

29.

Ibraheem K, Yhmed AMA, Qayyum T, Bryan NP, Georgopoulos NT. CD40 induces renal cell carcinoma-specific differential regulation of TRAF proteins, ASK1 activation and JNK/p38-mediated, ROS-dependent mitochondrial apoptosis. Cell Death Discov. 2019;5(1):148. https://doi.org/10.1038/s41420-019-0229-8.CrossRefPubMedPubMedCentral

30.

Georgopoulos NT, Steele LP, Thomson MJ, Selby PJ, Southgate J, Trejdosiewicz LK. A novel mechanism of CD40-induced apoptosis of carcinoma cells involving TRAF3 and JNK/AP-1 activation. Cell Death Differ. 2006;13(10):1789–801. https://doi.org/10.1038/sj.cdd.4401859.CrossRefPubMed

31.

Eliopoulos AG, Davies C, Knox PG, Gallagher NJ, Afford SC, Adams DH, et al. CD40 induces apoptosis in carcinoma cells through activation of cytotoxic ligands of the tumor necrosis factor superfamily. Mol Cell Biol. 2000;20(15):5503–15. https://doi.org/10.1128/MCB.20.15.5503-5515.2000.CrossRefPubMedPubMedCentral

32.

Qiu X, Klausen C, Cheng JC, Leung PC. CD40 ligand induces RIP1-dependent, necroptosis-like cell death in low-grade serous but not serous borderline ovarian tumor cells. Cell Death Dis. 2015;6(8):e1864. https://doi.org/10.1038/cddis.2015.229.CrossRefPubMedPubMedCentral

33.

Hill SC, Youde SJ, Man S, Teale GR, Baxendale AJ, Hislop A, et al. Activation of CD40 in cervical carcinoma cells facilitates CTL responses and augments chemotherapy-induced apoptosis. J Immunol. 2005;174(1):41–50. https://doi.org/10.4049/jimmunol.174.1.41.CrossRefPubMed

34.

Knox PG, Davies CC, Ioannou M, Eliopoulos AG. The death domain kinase RIP1 links the immunoregulatory CD40 receptor to apoptotic signaling in carcinomas. J Cell Biol. 2011;192(3):391–9. https://doi.org/10.1083/jcb.201003087.CrossRefPubMedPubMedCentral

35.

Pirozzi G, Lombari V, Zanzi D, Ionna F, Lombardi ML, Errico S, et al. CD40 expressed on human melanoma cells mediates T cell co-stimulation and tumor cell growth. Int Immunol. 2000;12(6):787–95. https://doi.org/10.1093/intimm/12.6.787.CrossRefPubMed

36.

Forbes SA, Bhamra G, Bamford S, Dawson E, Kok C, Clements J, Menzies A, Teague JW, Futreal PA, Stratton MR: The catalogue of somatic mutations in cancer (COSMIC). Curr Protoc Hum Genet 2008, Chapter 10:Unit 10–11.

37.

Farooqi AA, Li KT, Fayyaz S, Chang YT, Ismail M, Liaw CC, et al. Anticancer drugs for the modulation of endoplasmic reticulum stress and oxidative stress. Tumour Biol. 2015;36(8):5743–52. https://doi.org/10.1007/s13277-015-3797-0.CrossRefPubMed

38.

Ritt DA, Abreu-Blanco MT, Bindu L, Durrant DE, Zhou M, Specht SI, et al. Inhibition of Ras/Raf/MEK/ERK pathway signaling by a stress-induced phospho-regulatory circuit. Mol Cell. 2016;64(5):875–87. https://doi.org/10.1016/j.molcel.2016.10.029.CrossRefPubMedPubMedCentral

39.

Aaes TL, Vandenabeele P. The intrinsic immunogenic properties of cancer cell lines, immunogenic cell death, and how these influence host antitumor immune responses. Cell Death Differ. 2021;28(3):843–60. https://doi.org/10.1038/s41418-020-00658-y.CrossRefPubMed

40.

Waithman J, Gebhardt T, Bedoui S. Skin tumor immunity: site does matter for antigen presentation by DCs. Eur J Immunol. 2016;46(3):543–6. https://doi.org/10.1002/eji.201646293.CrossRefPubMed

41.

Choi J, Beaino W, Fecek RJ, Fabian KPL, Laymon CM, Kurland BF, et al. Combined VLA-4-targeted radionuclide therapy and immunotherapy in a mouse model of melanoma. J Nucl Med. 2018;59(12):1843–9. https://doi.org/10.2967/jnumed.118.209510.CrossRefPubMedPubMedCentral

42.

Meng Y, Harlin H, O'Keefe JP, Gajewski TF. Induction of cytotoxic granules in human memory CD8+ T cell subsets requires cell cycle progression. J Immunol. 2006;177(3):1981–7. https://doi.org/10.4049/jimmunol.177.3.1981.CrossRefPubMed

43.

LaFleur MW, Muroyama Y, Drake CG, Sharpe AH. Inhibitors of the PD-1 pathway in tumor therapy. J Immunol. 2018;200(2):375–83. https://doi.org/10.4049/jimmunol.1701044.CrossRefPubMed

44.

Khan AR, Hams E, Floudas A, Sparwasser T, Weaver CT, Fallon PG. PD-L1hi B cells are critical regulators of humoral immunity. Nat Commun. 2015;6(1):5997. https://doi.org/10.1038/ncomms6997.CrossRefPubMed

45.

Guan H, Lan Y, Wan Y, Wang Q, Wang C, Xu L, et al. PD-L1 mediated the differentiation of tumor-infiltrating CD19(+) B lymphocytes and T cells in invasive breast cancer. Oncoimmunology. 2016;5(2):e1075112. https://doi.org/10.1080/2162402X.2015.1075112.CrossRefPubMed

46.

Yang J, Yan C, Vilgelm AE, Chen SC, Ayers GD, Johnson CA, et al. Targeted deletion of CXCR2 in myeloid cells alters the tumor immune environment to improve antitumor immunity. Cancer Immunol Res. 2021;9(2):200–13. https://doi.org/10.1158/2326-6066.CIR-20-0312.CrossRefPubMed

47.

Cunningham AF, Flores-Langarica A, Bobat S, Dominguez Medina CC, Cook CN, Ross EA, et al. B1b cells recognize protective antigens after natural infection and vaccination. Front Immunol. 2014;5:535.CrossRefPubMedPubMedCentral

48.

Yang J, Hawkins OE, Barham W, Gilchuk P, Boothby M, Ayers GD, et al. Myeloid IKKbeta promotes antitumor immunity by modulating CCL11 and the innate immune response. Cancer Res. 2014;74(24):7274–84. https://doi.org/10.1158/0008-5472.CAN-14-1091.CrossRefPubMedPubMedCentral

49.

Yang Y, Wilson JM. CD40 ligand-dependent T cell activation: requirement of B7-CD28 signaling through CD40. Science. 1996;273(5283):1862–4. https://doi.org/10.1126/science.273.5283.1862.CrossRefPubMed

50.

Bugeon L, Dallman MJ. Costimulation of T cells. Am J Respir Crit Care Med. 2000;162(supplement_3):S164–8. https://doi.org/10.1164/ajrccm.162.supplement_3.15tac5.CrossRefPubMed

51.

Shattuck-Brandt RL, Chen SC, Murray E, Johnson CA, Crandall H, O'Neal JF, et al. Metastatic melanoma patient-derived xenografts respond to mdm2 inhibition as a single agent or in combination with BRAF/MEK inhibition. Clin Cancer Res. 2020;26(14):3803–18. https://doi.org/10.1158/1078-0432.CCR-19-1895.CrossRefPubMedPubMedCentral

52.

Chen PL, Roh W, Reuben A, Cooper ZA, Spencer CN, Prieto PA, et al. Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer Discov. 2016;6(8):827–37. https://doi.org/10.1158/2159-8290.CD-15-1545.CrossRefPubMedPubMedCentral

53.

Riaz N, Havel JJ, Makarov V, Desrichard A, Urba WJ, Sims JS, et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell. 2017;171(4):934–49 e916. https://doi.org/10.1016/j.cell.2017.09.028.CrossRefPubMedPubMedCentral

54.

Jerby-Arnon L, Shah P, Cuoco MS, Rodman C, Su MJ, Melms JC, et al. A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell. 2018;175(4):984–97 e924. https://doi.org/10.1016/j.cell.2018.09.006.CrossRefPubMedPubMedCentral

55.

Baker SJ, Cosenza SC, Athuluri-Divakar S, Reddy MVR, Carpio RV, Jain R, Aggarwal AK, Reddy EP. Mechanism of action of rigosertib does not involve tubulin binding. BioRxiv 2019.

56.

Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7(2):27–31. https://doi.org/10.4103/0976-0105.177703.CrossRefPubMedPubMedCentral

57.

Fogarty CE, Bergmann A. Killers creating new life: caspases drive apoptosis-induced proliferation in tissue repair and disease. Cell Death Differ. 2017;24(8):1390–400. https://doi.org/10.1038/cdd.2017.47.CrossRefPubMedPubMedCentral

58.

Diwanji N, Bergmann A. An unexpected friend - ROS in apoptosis-induced compensatory proliferation: implications for regeneration and cancer. Semin Cell Dev Biol. 2018;80:74–82. https://doi.org/10.1016/j.semcdb.2017.07.004.CrossRefPubMed

59.

Dunnill CJ, Ibraheem K, Mohamed A, Southgate J, Georgopoulos NT. A redox state-dictated signalling pathway deciphers the malignant cell specificity of CD40-mediated apoptosis. Oncogene. 2017;36(18):2515–28. https://doi.org/10.1038/onc.2016.401.CrossRefPubMed

60.

Beatty GL, Li Y, Long KB. Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists. Expert Rev Anticancer Ther. 2017;17(2):175–86. https://doi.org/10.1080/14737140.2017.1270208.CrossRefPubMed

61.

Long KB, Gladney WL, Tooker GM, Graham K, Fraietta JA, Beatty GL. IFNgamma and CCL2 cooperate to redirect tumor-infiltrating monocytes to degrade fibrosis and enhance chemotherapy efficacy in pancreatic carcinoma. Cancer Discov. 2016;6(4):400–13. https://doi.org/10.1158/2159-8290.CD-15-1032.CrossRefPubMedPubMedCentral

62.

Singh M, Vianden C, Cantwell MJ, Dai Z, Xiao Z, Sharma M, et al. Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain. Nat Commun. 2017;8(1):1447. https://doi.org/10.1038/s41467-017-01572-7.CrossRefPubMedPubMedCentral

63.

Dempke WCM, Fenchel K, Uciechowski P, Dale SP. Second- and third-generation drugs for immuno-oncology treatment-the more the better? Eur J Cancer. 2017;74:55–72. https://doi.org/10.1016/j.ejca.2017.01.001.CrossRefPubMed

64.

Irenaeus SMM, Nielsen D, Ellmark P, Yachnin J, Deronic A, Nilsson A, et al. First-in-human study with intratumoral administration of a CD40 agonistic antibody, ADC-1013, in advanced solid malignancies. Int J Cancer. 2019;145(5):1189–99. https://doi.org/10.1002/ijc.32141.CrossRefPubMed

65.

Knorr DA, Dahan R, Ravetch JV. Toxicity of an fc-engineered anti-CD40 antibody is abrogated by intratumoral injection and results in durable antitumor immunity. Proc Natl Acad Sci U S A. 2018;115(43):11048–53. https://doi.org/10.1073/pnas.1810566115.CrossRefPubMedPubMedCentral

66.

Litchfield K, Reading JL, Puttick C, Thakkar K, Abbosh C, Bentham R, et al. Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell. 2021;184(3):596–614 e514. https://doi.org/10.1016/j.cell.2021.01.002.CrossRefPubMedPubMedCentral

67.

Jost M, Chen Y, Gilbert LA, Horlbeck MA, Krenning L, Menchon G, et al. Combined CRISPRi/a-based chemical genetic screens reveal that rigosertib is a microtubule-destabilizing agent. Mol Cell. 2017;68(1):210–23 e216. https://doi.org/10.1016/j.molcel.2017.09.012.CrossRefPubMedPubMedCentral

68.

Jost M, Chen Y, Gilbert LA, Horlbeck MA, Krenning L, Menchon G, et al. Pharmaceutical-grade rigosertib is a microtubule-destabilizing agent. Mol Cell. 2020;79(1):191–8 e193. https://doi.org/10.1016/j.molcel.2020.06.008.CrossRefPubMedPubMedCentral

69.

Vilgelm AE, Pawlikowski JS, Liu Y, Hawkins OE, Davis TA, Smith J, et al. Mdm2 and aurora kinase a inhibitors synergize to block melanoma growth by driving apoptosis and immune clearance of tumor cells. Cancer Res. 2015;75(1):181–93. https://doi.org/10.1158/0008-5472.CAN-14-2405.CrossRefPubMed

70.

Yang J, Kumar A, Vilgelm AE, Chen SC, Ayers GD, Novitskiy SV, et al. Loss of CXCR4 in myeloid cells enhances antitumor immunity and reduces melanoma growth through NK cell and FASL mechanisms. Cancer Immunol Res. 2018;6(10):1186–98. https://doi.org/10.1158/2326-6066.CIR-18-0045.CrossRefPubMedPubMedCentral

71.

Olivo Pimentel V, Yaromina A, Marcus D, Dubois LJ, Lambin P. A novel co-culture assay to assess anti-tumor CD8(+) T cell cytotoxicity via luminescence and multicolor flow cytometry. J Immunol Methods. 2020;487:112899. https://doi.org/10.1016/j.jim.2020.112899.CrossRefPubMed

72.

Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. https://doi.org/10.1186/s13059-014-0550-8.CrossRefPubMedPubMedCentral

73.

LBenjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statist Soc B. 1995;57(1):289-300.

Title: Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade
Authors: Chi Yan
Nabil Saleh
Jinming Yang
Caroline A. Nebhan
Anna E. Vilgelm
E. Premkumar Reddy
Joseph T. Roland
Douglas B. Johnson
Sheau-Chiann Chen
Rebecca L. Shattuck-Brandt
Gregory D. Ayers
Ann Richmond
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Melanoma
Melanoma
Published in: Molecular Cancer / Issue 1/2021
Electronic ISSN: 1476-4598
DOI: https://doi.org/10.1186/s12943-021-01366-y

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Trial registration

Graphical abstract

Please log in to get access to this content

Other articles of this Issue 1/2021

Correction to: ciRS-7 is a prognostic biomarker and potential gene therapy target for renal cell carcinoma

Platelets, immune cells and the coagulation cascade; friend or foe of the circulating tumour cell?

Nonsense-mediated RNA decay and its bipolar function in cancer

The inflammatory kinase IKKα phosphorylates and stabilizes c-Myc and enhances its activity

PARP inhibitor Olaparib overcomes Sorafenib resistance through reshaping the pluripotent transcriptome in hepatocellular carcinoma

Pan-cancer characterization of expression and clinical relevance of m6A-related tissue-elevated long non-coding RNAs

Keynote webinar | Spotlight on antibody–drug conjugates in cancer