PD-L1 and TILS Predict Resistance in BRAF-Treated Melanoma Patients

MedicalResearch.com Interview with:
Mario Mandalà, MD
Department of Oncology and Haematology
Papa Giovanni XXIII Hospital
Bergamo, Italy

Medical Research: What is the background for this study?

Dr. Mandalà: In addition to their established molecular mechanism of action, growing evidence suggests that the therapeutic efficacy of BRAFi relies on additional factors that affect the tumor–host interactions, including the enhancement of melanoma antigen expression and the increase in immune response against tumor cells.  Preclinical data show that oncogenic BRAF contributes to immune evasion, and that targeting this mutation may increase the melanoma immunogenicity. Data in vitro or from animal models propose PD-L1 as a potential mechanism that favors BRAFi resistance through the modulation of host immune responses. However, demonstration of this hypothesis in the clinical setting is lacking.

Medical Research: What are the main findings?

Dr. Mandalà: In the present study, we have evaluated, in a homogeneous series of MMP treated with BRAFi, the association of tumoral PD-L1 IHC expression and the density of TIMC with RR, PFS and OS. Results provide the first proof-of-principle clinical evidence of the predictive and prognostic relevance of PD-L1 IHC expression and density of immune cell infiltration in BRAFV600 mutated MMP receiving BRAFi.

Medical Research: What should clinicians and patients take away from your report?

Dr. Mandalà: The most striking finding of this study is that IHC PD-L1 overexpression, together with the lack  of  TIMC in metastatic melanoma samples, are associated with resistance and poor prognosis in MMP receiving BRAFi. A limitation of our study is that in our patient cohort, no patient received BRAF and MEK inhibitors, which are now known to improve RR, PFS and OS, as compared to BRAFi alone. Furthermore we did not evaluate the immunophenotype of immune cell infiltration, and the absence of CD8 staining that has been widely used in previous studies in association with PD-L1 expression and could give more quantitative and reliable results regarding the immune infiltrate.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Mandalà: Since PD-L1 overexpressing melanoma patients are at higher risk of developing early progression and worse outcome than those who are PD-L1 negative, a different strategy should probably be pursued in these patients. Whether starting with anti PD-1 antibodies may result in a better outcome should be evaluated in ad hoc designed studies, since PD-L1 positive melanomas with immune cell infiltration seem to benefit particularly from anti PD-1 antibodies


Massi, D. Brusa, B. Merelli, C. Falcone, G. Xue, A. Carobbio, R. Nassini, G. Baroni, E. Tamborini, L. Cattaneo, V. Audrito, S. Deaglio, and M. Mandalà

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 first published online June 2, 2015 doi:10.1093/annonc/mdv255

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Mario Mandalà, MD, & Department of Oncology and Haematology (2015). PD-L1 and TILS Predict Resistance in BRAF-Treated Melanoma Patients