The density and spatial tissue distribution of CD8+ and CD163+ immune cells predict response and outcome in melanoma patients receiving MAPK inhibitors
Tóm tắt
Clinical response to MAPK inhibitors in metastatic melanoma patients is heterogeneous for reasons still needing to be elucidated. As the patient immune activity contributes to treatment clinical benefit, the pre-existing level of immunity at tumor site may provide biomarkers of disease outcome to therapy. Here we investigated whether assessing the density and spatial tissue distribution of key immune cells in the tumor microenvironment could identify patients predisposed to respond to MAPK inhibitors. Pretreatment tumor biopsies from a total of 213 patients (158 for the training set and 55 for the validation set) treated with BRAF or BRAF/MEK inhibitors within the Italian Melanoma Intergroup were stained with selected immune markers (CD8, CD163, β-catenin, PD-L1, PD-L2). Results, obtained by blinded immunohistochemical scoring and digital image analysis, were correlated with clinical response and outcome by multivariate logistic models on response to treatment and clinical outcome, adjusted for American Joint Committee on Cancer stage, performance status, lactate dehydrogenase and treatment received. Patients with high intratumoral, but not peritumoral, CD8+ T cells and concomitantly low CD163+ myeloid cells displayed higher probability of response (OR 9.91, 95% CI 2.23–44.0, p = 0.003) and longer overall survival (HR 0.34, 95% CI 0.16–0.72, p = 0.005) compared to those with intratumoral low CD8+ T cells and high CD163+ myeloid cells. The latter phenotype was instead associated with a shorter progression free survival (p = 0.010). In contrast, PD-L1 and PD-L2 did not correlate with clinical outcome while tumor β-catenin overexpression showed association with lower probability of response (OR 0.48, 95% CI 0.21–1.06, p = 0.068). Analysis of the spatially constrained distribution of CD8+ and CD163+ cells, representative of the opposite circuits of antitumor vs protumor immunity, respectively, may assist in identifying melanoma patients with improved response and better outcome upon treatment with MAPK inhibitors. These data underline the role of endogenous immune microenvironment in predisposing metastatic melanoma patients to benefit from therapies targeting driver-oncogenic pathways.
Tài liệu tham khảo
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.
Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–65.
Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444–51.
Ascierto PA, McArthur GA, Dreno B, Atkinson V, Liszkay G, Di Giacomo AM, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17(9):1248–60.
Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5):603–15.
Long GV, Eroglu Z, Infante J, Patel S, Daud A, Johnson DB, et al. Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma who received Dabrafenib combined with Trametinib. J Clin Oncol. 2018;36(7):667–73.
Mandalà M, De Logu F, Merelli B, Nassini R, Massi D. Immunomodulating property of MAPK inhibitors: from translational knowledge to clinical implementation. Lab Investig. 2017;97(2):166–75.
Winder M, Virós A. Mechanisms of drug resistance in melanoma. Handb Exp Pharmacol. 2018;249:91–108.
Yan Y, Robert C, Larkin J, Ascierto PA, Dreno B, Maio M, et al. Genomic features of complete responders (CR) versus fast progressors (PD) in patients with BRAFV600-mutated metastatic melanoma treated with cobimetinib + vemurafenib or vemurafenib alone. Clin Cancer Res. 2019;25(11):3239–46.
Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature. 2015;523(7559):231–5.
Hugo W, Shi H, Sun L, Piva M, Song C, Kong X, et al. Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell. 2015;162(6):1271–85.
Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, Ferrone CR, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19(5):1225–31.
Wilmott JS, Long GV, Howle JR, Haydu LE, Sharma RN, Thompson JF, et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res. 2012;18(5):1386–94.
Liu L, Mayes PA, Eastman S, Shi H, Yadavilli S, Zhang T, et al. The BRAF and MEK inhibitors Dabrafenib and Trametinib: effects on immune function and in combination with Immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4. Clin Cancer Res. 2015;21(7):1639–51.
Steinberg SM, Shabaneh TB, Zhang P, Martyanov V, Li Z, Malik BT, et al. Myeloid cells that impair immunotherapy are restored in melanomas which acquire resistance to BRAF inhibitors. Cancer Res. 2017;77(7):1599–610.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.
Larkin J, Del Vecchio M, Ascierto PA, Krajsova I, Schachter J, Neyns B, et al. Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol. 2014;15(4):436–44.
Massi D, Romano E, Rulli E, Merelli B, Nassini R, De Logu F, et al. Baseline beta-catenin, programmed death-ligand 1 expression and tumour-infiltrating lymphocytes predict response and poor prognosis in BRAF inhibitor-treated melanoma patients. Eur J Cancer. 2017;78:70–81.
Massi D, Brusa D, Merelli B, Falcone C, Xue G, Carobbio A, et al. The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600. Ann Oncol. 2015;26(9):1980–7.
Schadendorf D, Long GV, Stroiakovski D, Karaszewska B, Hauschild A, Levchenko E, et al. Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials. Eur J Cancer. 2017;82:45–55.
Osgood C, Mulkey F, Mishra-Kalyani PS, Lemery S, Ward A, Keegan P, et al. U.S. Food and Drug Administration, Silver Spring, MD FDA analysis of depth of response (DpR) and survival across 10 randomized controlled trials in patients with previously untreated unresectable or metastatic melanoma (UMM) by therapy type. J Clin Oncol 2019; 37 Suppl: 9508.
Wargo JA, Cooper ZA, Flaherty KT. Universes collide: combining immunotherapy with targeted therapy for cancer. Cancer Discov. 2014;4(12):1377–86.
Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17(13):4550–7.
Ladanyi A. Prognostic and predictive significance of immune cells infiltrating cutaneous melanoma. Pigment Cell Melanoma Res. 2015;28(5):490–500.
Smith MP, Sanchez-Laorden B, O'Brien K, Brunton H, Ferguson J, Young H, et al. The immune microenvironment confers resistance to MAPK pathway inhibitors through macrophage-derived TNFalpha. Cancer Discov. 2014;4(10):1214–29.
Smith MP, Wellbrock C. Molecular pathways: maintaining MAPK inhibitor sensitivity by targeting nonmutational tolerance. Clin Cancer Res. 2016;22(24):5966–70.
Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14(7):399–416.
Mallett S, Timmer A, Sauerbrei W, Altman DG. Reporting of prognostic studies of tumour markers: a review of published articles in relation to REMARK guidelines. Br J Cancer. 2010;102(1):173–80.
Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014;74(18):5057–69.